JP5281291B2 - New compounds - Google Patents

Abstract

The present invention is directed to compounds of formula (I): wherein R1 represents C4-C7 branched alkyl group, a bicycloalkyl group, or a C5-C6 cycloalkyl which optionally may be substituted with a C1-C4 alkyl group; R2 represents hydrogen, a methyl group, which may be in either the alpha or beta configuration, or a methylene group; R3 and R4 are the same or a different group and each independently represents hydrogen, halogen or a methyl group; <img id="CUSTOM-CHARACTER-00001" he="2.79mm" wi="4.23mm" file="US07579335-20090825-P00001.TIF" alt="custom character" img-content="character" img-format="tif"/> represents a single or a double bond; and physiologically acceptable solvates thereof, physiologically functional derivatives thereof, pharmaceutical compositions comprising the compounds, the use of the compounds for the manufacture of medicaments particularly for the treatment of inflammatory and/or allergic conditions, processes for the preparation of the compounds, and chemical intermediates in the processes for the manufacture of the compounds.

Description

  The present invention relates to compounds that are androstane series glucocorticoid receptor agonists, and methods for producing them. The invention also relates to pharmaceutical preparations containing the compounds and their therapeutic use, in particular for the treatment of inflammatory and allergic conditions.

  Glucocorticosteroids with anti-inflammatory properties are known and widely used for the treatment of inflammatory disorders or diseases such as asthma or rhinitis. Androstane 17α-carbonate compounds which are said to have anti-inflammatory activity are disclosed in US Pat. No. 4,996,335. Drugs of Today 2000, 36 (5), 313-320 discloses loteprednol etabonate for treating allergic airway diseases. The inventors have identified a novel series of androstane 17α-carbonate derivatives.

Thus, according to one embodiment of the present invention, a compound of formula (I):

は単結合又は二重結合を示す）；
又はその生理的に許容される溶媒和物が提供される。 (Where
R ₁ represents a C ₄ -C ₇ branched alkyl group, a bicycloalkyl group, or a C ₅ -C ₆ cycloalkyl group optionally substituted with a C ₁ -C ₄ alkyl group;
R ₂ represents hydrogen, a methyl group which may be either α or β configuration, or a methylene group;
R ₃ and R ₄ are the same or different groups and each independently represents a hydrogen, halogen or methyl group;
And

Represents a single bond or a double bond);
Or a physiologically acceptable solvate thereof.

  Examples of solvates include hydrates.

  In the following, reference to a compound according to the invention includes both the compound of formula (I) and its solvates.

In some embodiments of the present invention, preferred examples of the C ₄ -C ₇ branched alkyl group that R ₁ may represent include 1,1-dimethylethyl, 1-ethylpropyl, 1,1-dimethylpropyl, 2 , 2-dimethylpropyl, 1,2-dimethylpropyl, 1-ethyl-2-methylpropyl, 2-methyl-1- (1-methylethyl) propyl, 2-ethylbutyl, 1-propylbutyl or 1- (1- Includes methylethyl) butyl group.

In another embodiment of the present invention, preferred examples of the C ₄ -C ₇ branched alkyl group that R ₁ may represent include 1,1-dimethylethyl, 1-ethylpropyl, 1,1-dimethylpropyl, 2, Including 2-dimethylpropyl, 1,2-dimethylpropyl, 1-ethyl-2-methylpropyl, 2-methyl-1- (1-methylethyl) propyl or 2-ethylbutyl.

Preferred examples of the bicycloalkyl group that R ₁ may represent include a (1RS, 2SR, 4SR) -bicyclo [2.2.1] hept-2-yl group.

Preferred examples of the bicycloalkyl group that R ₁ may represent are (1RS, 2RS, 4SR) -bicyclo [2.2.1] hept-2-yl, (1RS, 2SR, 4SR) -bicyclo [2.2.1] hept-2 -Yl, (1S, 2R, 4S) -1,7,7-trimethylbicyclo [2.2.1] hept-2-yl or (1R, 2S, 4R) -1,7,7-trimethylbicyclo [2.2.1 ] Includes a hepta-2-yl group.

In one embodiment, R ₁ represents a C ₅ -C ₆ cycloalkyl group optionally substituted with a C ₁ -C ₃ alkyl group.

Preferred examples of optionally substituted C ₅ -C ₆ cycloalkyl groups that R ₁ may represent include cyclopentyl, (1SR, 2RS) -2-methylcyclohexyl or 4- (1-methylethyl) cyclohexyl groups.

Preferred examples of optionally substituted C ₅ -C ₆ cycloalkyl groups that R ₁ may represent include cyclopentyl, (1SR, 2RS) -2-methylcyclohexyl, 4- (1-methylethyl) cyclohexyl, trans-4- Includes an ethylcyclohexyl or cis-4-ethylcyclohexyl group.

In some embodiments of the invention, more preferred groups that R ₁ may represent are 1,1-dimethylethyl, 1,1-dimethylpropyl, 1-ethylpropyl, 2-methyl-1- (1-methylethyl) ) Propyl, 2,2-dimethylpropyl, (1SR, 2RS) -2-methylcyclohexyl, 4- (1-methylethyl) cyclohexyl isomer B, (1RS, 2RS, 4SR) -bicyclo [2.2.1] hepta- Includes 2-yl or (1RS, 2SR, 4SR) -bicyclo [2.2.1] hept-2-yl groups.

In another embodiment of the invention, more preferred groups that R ₁ may represent are 1,1-dimethylethyl, 1,1-dimethylpropyl, 1-ethylpropyl, 2-methyl-1- (1-methylethyl) Propyl, 2,2-dimethylpropyl, (1SR, 2RS) -2-methylcyclohexyl, 4- (1-methylethyl) cyclohexyl or (1RS, 2SR, 4SR) -bicyclo [2.2.1] hept-2-yl group Is included.

Most preferred groups that R ₁ may represent include 1,1-dimethylpropyl, 1,1-dimethylethyl or (1RS, 2SR, 4SR) -bicyclo [2.2.1] hept-2-yl groups.

Examples of the most preferred group that R ₁ may represent include 1,1-dimethylpropyl group or 1,1-dimethylethyl group.

R ₂ preferably represents a methyl group, particularly methyl in the α configuration.

Preference is given to compounds of the formula (I) in which R ₃ and R ₄ which may be the same or different each represent hydrogen, methyl, fluorine or chlorine, in particular hydrogen or fluorine. Particularly preferred are compounds in which R ₃ and R ₄ are both fluorine.

は二重結合を示す。 Preferably,

Indicates a double bond.

  It should be understood that the invention extends to all combinations of preferred groups referred to above.

Compounds of formula (I) include the following:
(6α, 11β, 16α, 17α) -17-({[(1,1-dimethylethyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost- Cyanomethyl 1,4-diene-17-carboxylate;
(6α, 11β, 16α, 17α) -17-({[(1,1-dimethylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost- Cyanomethyl 1,4-diene-17-carboxylate;
(6α, 11β, 16α, 17α) -17-({[(1-Ethylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost-1, Cyanomethyl 4-diene-17-carboxylate;
(6α, 11β, 16α, 17α) -6,9-Difluoro-11-hydroxy-16-methyl-17-[({[2-methyl-1- (1-methylethyl) propyl] oxy} carbonyl) oxy] Cyanomethyl-3-oxoandrost-1,4-diene-17-carboxylate;
(6α, 11β, 16α, 17α) -17-({[(2-Ethylbutyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost-1,4 -Cyanomethyl diene-17-carboxylate;
(6α, 11β, 16α, 17α) -17-({[(2,2-dimethylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost- Cyanomethyl 1,4-diene-17-carboxylate;
(6α, 11β, 16α, 17α) -17-({[(1-Ethyl-2-methylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandro Sta-1,4-diene-17-carboxylate cyanomethyl;
(6α, 11β, 16α, 17α) -17-({[(1,2-dimethylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost- Cyanomethyl 1,4-diene-17-carboxylate; and
(6α, 11β, 16α, 17α) -17-{[(Cyclopentyloxy) carbonyl] oxy} -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost-1,4-diene-17 -Cyanomethyl carboxylate;
(6α, 11β, 16α, 17α) -6,9-Difluoro-11-hydroxy-16-methyl-17-[({[(1SR, 2RS) -2-methylcyclohexyl] oxy} carbonyl) oxy] -3- Oxoandrosta-1,4-diene-17-carboxylate cyanomethyl;
(6α, 11β, 16α, 17α) -6,9-Difluoro-11-hydroxy-16-methyl-17-[({[4- (1-methylethyl) cyclohexyl] oxy} carbonyl) oxy] -3-oxo Androsta-1,4-diene-17-carboxylate cyanomethyl;
(6α, 11β, 16α, 17α) -17-({[(1RS, 2RS, 4SR) -bicyclo [2.2.1] hept-2-yloxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy- Cyanomethyl 16-methyl-3-oxoandrosta-1,4-diene-17-carboxylate;
(6α, 11β, 16α, 17α) -17-({[(1RS, 2SR, 4SR) -bicyclo [2.2.1] hept-2-yloxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy- Cyanomethyl 16-methyl-3-oxoandrosta-1,4-diene-17-carboxylate;
(6α, 11β, 16α, 17α) -6,9-Difluoro-11-hydroxy-16-methyl-3-oxo-17-[({[(1S, 2R, 4S) -1,7,7-trimethylbicyclo [2.2.1] hept-2-yl] oxy} carbonyl) oxy] androsta-1,4-diene-17-carboxylate cyanomethyl;
(6α, 11β, 16α, 17α) -6,9-Difluoro-11-hydroxy-16-methyl-3-oxo-17-[({[(1R, 2S, 4R) -1,7,7-trimethylbicyclo [2.2.1] hept-2-yl] oxy} carbonyl) oxy] androsta-1,4-diene-17-carboxylate cyanomethyl;
(6α, 11β, 16α, 17α) -6,9-Difluoro-11-hydroxy-16-methyl-3-oxo-17-[({[(1R, 2R, 3R, 5S) -2,6,6- Trimethylbicyclo [3.1.1] hept-3-yl] oxy} carbonyl) oxy] androsta-1,4-diene-17-carboxylate cyanomethyl;
(6α, 11β, 16α, 17α) -6,9-Difluoro-11-hydroxy-16-methyl-3-oxo-17-[({[(1S, 2S, 3S, 5R) -2,6,6- Trimethylbicyclo [3.1.1] hept-3-yl] oxy} carbonyl) oxy] androsta-1,4-diene-17-carboxylate cyanomethyl;
(6α, 11β, 16α, 17α) -6,9-Difluoro-11-hydroxy-16-methyl-3-oxo-17-[({[(1R, 2R, 4S) -1,3,3-trimethylbicyclo [2.2.1] hept-2-yl] oxy} carbonyl) oxy] androsta-1,4-diene-17-carboxylate cyanomethyl;
(6α, 11β, 16α, 17α) -17-({[(trans-4-ethylcyclohexyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost- Cyanomethyl 1,4-diene-17-carboxylate;
(6α, 11β, 16α, 17α) -17-({[(cis-4-ethylcyclohexyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost- Cyanomethyl 1,4-diene-17-carboxylate;
(6α, 11β, 16α, 17α) -6,9-Difluoro-11-hydroxy-16-methyl-3-oxo-17-({[(1-propylbutyl) oxy] carbonyl} oxy) androsta-1, Cyanomethyl 4-diene-17-carboxylate;
(6α, 11β, 16α, 17α) -6,9-Difluoro-11-hydroxy-16-methyl-3-oxo-17-[({[(1R, 2R, 4R) -1,7,7-trimethylbicyclo [2.2.1] hept-2-yl] oxy} carbonyl) oxy] androsta-1,4-diene-17-carboxylate cyanomethyl;
(6α, 11β, 16α, 17α) -6,9-Difluoro-11-hydroxy-16-methyl-3-oxo-17-[({[(1S, 2S, 4S) -1,7,7-trimethylbicyclo [2.2.1] hept-2-yl] oxy} carbonyl) oxy] androsta-1,4-diene-17-carboxylate cyanomethyl;
(6α, 11β, 16α, 17α) -6,9-Difluoro-11-hydroxy-16-methyl-3-oxo-17-({[(1,2,2-trimethylpropyl) oxy] carbonyl} oxy) andro Sta-1,4-diene-17-carboxylate cyanomethyl; and
(6α, 11β, 16α, 17α) -6,9-Difluoro-11-hydroxy-16-methyl-17-[({[1- (1-methylethyl) butyl] oxy} carbonyl) oxy] -3-oxo Androsta-1,4-diene-17-carboxylate cyanomethyl.

In some embodiments of the invention, preferred compounds of formula (I) include:
(6α, 11β, 16α, 17α) -17-({[(1-Ethylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost-1, Cyanomethyl 4-diene-17-carboxylate;
(6α, 11β, 16α, 17α) -6,9-Difluoro-11-hydroxy-16-methyl-17-[({[2-methyl-1- (1-methylethyl) propyl] oxy} carbonyl) oxy] Cyanomethyl-3-oxoandrost-1,4-diene-17-carboxylate;
(6α, 11β, 16α, 17α) -6,9-Difluoro-11-hydroxy-16-methyl-17-[({[4- (1-methylethyl) cyclohexyl] oxy} carbonyl) oxy] -3-oxo Androsta-1,4-diene-17-carboxylate cyanomethyl;
(6α, 11β, 16α, 17α) -17-({[(2-Ethylbutyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost-1,4 -Cyanomethyl diene-17-carboxylate;
(6α, 11β, 16α, 17α) -6,9-Difluoro-11-hydroxy-16-methyl-17-[({[(1SR, 2RS) -2-methylcyclohexyl] oxy} carbonyl) oxy] -3- Oxoandrosta-1,4-diene-17-carboxylate cyanomethyl;
(6α, 11β, 16α, 17α) -17-({[(2,2-dimethylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost- Cyanomethyl 1,4-diene-17-carboxylate;
(6α, 11β, 16α, 17α) -17-({[(1RS, 2RS, 4SR) -bicyclo [2.2.1] hept-2-yloxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy- Cyanomethyl 16-methyl-3-oxoandrosta-1,4-diene-17-carboxylate;
(6α, 11β, 16α, 17α) -17-({[(1RS, 2SR, 4SR) -bicyclo [2.2.1] hept-2-yloxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy- Cyanomethyl 16-methyl-3-oxoandrosta-1,4-diene-17-carboxylate;
(6α, 11β, 16α, 17α) -17-({[(1,1-dimethylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost- Cyanomethyl 1,4-diene-17-carboxylate;
(6α, 11β, 16α, 17α) -17-({[(1,1-dimethylethyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost- Cyanomethyl 1,4-diene-17-carboxylate;
(6α, 11β, 16α, 17α) -17-({[(1-Ethyl-2-methylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandro Sta-1,4-diene-17-carboxylate cyanomethyl;
(6α, 11β, 16α, 17α) -17-({[(1,2-dimethylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost- Cyanomethyl 1,4-diene-17-carboxylate; and
(6α, 11β, 16α, 17α) -17-{[(Cyclopentyloxy) carbonyl] oxy} -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost-1,4-diene-17 -Cyanomethyl carboxylate.

In another embodiment of the present invention, preferred compounds of formula (I) include:
(6α, 11β, 16α, 17α) -17-({[(1,1-dimethylethyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost- Cyanomethyl 1,4-diene-17-carboxylate;
(6α, 11β, 16α, 17α) -17-({[(1,1-dimethylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost- Cyanomethyl 1,4-diene-17-carboxylate;
(6α, 11β, 16α, 17α) -17-({[(1-Ethylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost-1, Cyanomethyl 4-diene-17-carboxylate;
(6α, 11β, 16α, 17α) -6,9-Difluoro-11-hydroxy-16-methyl-17-[({[2-methyl-1- (1-methylethyl) oxy] carbonyl} oxy) -3 -Cyanomethyl oxoandrosta-1,4-diene-17-carboxylate;
(6α, 11β, 16α, 17α) -17-({[(1-Ethylbutyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost-1,4 -Cyanomethyl diene-17-carboxylate;
(6α, 11β, 16α, 17α) -17-({[(2,2-dimethylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost- Cyanomethyl 1,4-diene-17-carboxylate;
(6α, 11β, 16α, 17α) -17-({[(1-Ethyl-2-methylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandro Sta-1,4-diene-17-carboxylate cyanomethyl;
(6α, 11β, 16α, 17α) -17-({[(1,2-dimethylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost- Cyanomethyl 1,4-diene-17-carboxylate; and
(6α, 11β, 16α, 17α) -17-{[(Cyclopentyloxy) carbonyl] oxy} -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost-1,4-diene-17 -Cyanomethyl carboxylate.

(6α, 11β, 16α, 17α) -6,9-Difluoro-11-hydroxy-16-methyl-17-[({[(1SR, 2RS) -2-methylcyclohexyl] oxy} carbonyl) oxy] -3- Oxoandrosta-1,4-diene-17-carboxylate cyanomethyl;
(6α, 11β, 16α, 17α) -6,9-Difluoro-11-hydroxy-16-methyl-17-[({[4- (1-methylethyl) cyclohexyl] oxy} carbonyl} oxy) -3-oxo Androsta-1,4-diene-17-carboxylate cyanomethyl;
(6α, 11β, 16α, 17α) -17-({[(1RS, 2RS, 4SR) -bicyclo [2.2.1] hept-2-yloxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy- Cyanomethyl 16-methyl-3-oxoandrosta-1,4-diene-17-carboxylate;
(6α, 11β, 16α, 17α) -17-({[(1RS, 2SR, 4SR) -bicyclo [2.2.1] hept-2-yloxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy- Cyanomethyl 16-methyl-3-oxoandrosta-1,4-diene-17-carboxylate;
(6α, 11β, 16α, 17α) -6,9-Difluoro-11-hydroxy-16-methyl-3-oxo-17-[({[(1SR, 2RS) -1,7,7-trimethylbicyclo [2.2 .1] hept-2-yloxy] carbonyl} oxy) androsta-1,4-diene-17-carboxylate;
(6α, 11β, 16α, 17α) -6,9-Difluoro-11-hydroxy-16-methyl-3-oxo-17-[({[(1R, 2S, 4R) -1,7,7-trimethylbicyclo [2.2.1] hept-2-yl] oxy} carbonyl) oxy] androsta-1,4-diene-17-carboxylate cyanomethyl;
(6α, 11β, 16α, 17α) -17-({[(trans-4-ethylcyclohexyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost- Cyanomethyl 1,4-diene-17-carboxylate;
(6α, 11β, 16α, 17α) -17-({[(cis-4-ethylcyclohexyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost- Cyanomethyl 1,4-diene-17-carboxylate;
(6α, 11β, 16α, 17α) -6,9-Difluoro-11-hydroxy-16-methyl-3-oxo-17-({[(1-propylbutyl) oxy] carbonyl} oxy) androsta-1, Cyanomethyl 4-diene-17-carboxylate; and
(6α, 11β, 16α, 17α) -6,9-Difluoro-11-hydroxy-16-methyl-17-[({[1- (1-methylethyl) butyl] oxy} carbonyl) oxy] -3-oxo Androsta-1,4-diene-17-carboxylate cyanomethyl.

More preferred compounds of formula (I) are:
(6α, 11β, 16α, 17α) -17-({[(1,1-dimethylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost- Cyanomethyl 1,4-diene-17-carboxylate;
(6α, 11β, 16α, 17α) -17-({[(1,1-dimethylethyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost- Cyanomethyl 1,4-diene-17-carboxylate;
(6α, 11β, 16α, 17α) -17-({[(1-Ethylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost-1, Cyanomethyl 4-diene-17-carboxylate;
(6α, 11β, 16α, 17α) -6,9-Difluoro-11-hydroxy-16-methyl-17-[({[2-methyl-1- (1-methylethyl) propyl] oxy} carbonyl) oxy] Cyanomethyl-3-oxoandrost-1,4-diene-17-carboxylate;
(6α, 11β, 16α, 17α) -17-({[(2,2-dimethylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost- Cyanomethyl 1,4-diene-17-carboxylate;
(6α, 11β, 16α, 17α) -6,9-Difluoro-11-hydroxy-16-methyl-17-[({[(1SR, 2RS) -2-methylcyclohexyl] oxy} carbonyl) oxy] -3- Oxoandrosta-1,4-diene-17-carboxylate cyanomethyl;
(6α, 11β, 16α, 17α) -6,9-Difluoro-11-hydroxy-16-methyl-17-[({[4- (1-methylethyl) cyclohexyl] oxy} carbonyl) oxy] -3-oxo Androsta-1,4-diene-17-carboxylate cyanomethyl isomer B;
(6α, 11β, 16α, 17α) -17-({[(1RS, 2RS, 4SR) -bicyclo [2.2.1] hept-2-yloxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy- Cyanomethyl 16-methyl-3-oxoandrosta-1,4-diene-17-carboxylate; and
(6α, 11β, 16α, 17α) -17-({[(1RS, 2SR, 4SR) -bicyclo [2.2.1] hept-2-yloxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy- Cyanomethyl 16-methyl-3-oxoandrosta-1,4-diene-17-carboxylate.

In some embodiments of the present invention, the most preferred compounds include:
(6α, 11β, 16α, 17α) -17-({[(1,1-dimethylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost- Cyanomethyl 1,4-diene-17-carboxylate;
(6α, 11β, 16α, 17α) -17-({[(1,1-dimethylethyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost- Cyanomethyl 1,4-diene-17-carboxylate; and
(6α, 11β, 16α, 17α) -17-({[(1RS, 2SR, 4SR) -bicyclo [2.2.1] hept-2-yloxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy- Cyanomethyl 16-methyl-3-oxoandrosta-1,4-diene-17-carboxylate.

In another embodiment of the invention, the most preferred compounds are:
(6α, 11β, 16α, 17α) -17-({[(1,1-dimethylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost- Cyanomethyl 1,4-diene-17-carboxylate; and
(6α, 11β, 16α, 17α) -17-({[(1,1-dimethylethyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost- Cyanomethyl 1,4-diene-17-carboxylate.

  The compounds of formula (I) of the present invention are potentially beneficial, especially in topical administration, e.g., due to their ability to bind to the glucocorticoid receptor and not allow reaction through that receptor. Has anti-inflammatory or anti-allergic effects. Accordingly, the compounds of formula (I) are potentially useful in the treatment of inflammatory and / or allergic disorders.

  Examples of disease states in which the compounds of the present invention may have utility are skin diseases such as eczema, psoriasis, allergic dermatitis, neurodermatitis, pruritus and hypersensitivity reactions; nasal, throat or lung inflammatory conditions such as Asthma (including allergen-induced asthmatic reactions), rhinitis (including hay fever), nasal polyps, chronic obstructive pulmonary disease, interstitial pneumonia and fibrosis; inflammatory bowel symptoms such as ulcerative colitis and clones Disease; as well as autoimmune diseases such as rheumatoid arthritis.

  The compounds of the invention can also be used for the treatment of conjunctiva and conjunctivitis.

  It will be appreciated by those skilled in the art that reference herein to treatment extends to prophylaxis as well as treatment of established symptoms.

  As mentioned above, the compounds of formula (I) may be useful in human or veterinary medicine, in particular as anti-inflammatory and anti-allergic agents.

  Accordingly, as another aspect of the present invention, a compound of formula (I) or a physiologically acceptable thereof for use in human or veterinary medicine, particularly in the treatment of patients with inflammatory and / or allergic conditions Solvates are provided.

  According to another aspect of the present invention there is provided the use of a compound of formula (I) or a physiologically acceptable solvate thereof for the manufacture of a medicament for the treatment of patients with inflammatory and / or allergic conditions. Is done.

  In another or alternative embodiment, a method of treating a human or animal subject with an inflammatory and / or allergic condition, said human or animal subject having an effective amount of a compound of formula (I) or a physiologically acceptable There is provided a method of treatment as described above comprising administering a solvate to be treated.

  The compounds according to the invention can be formulated for administration in any convenient way, so the invention also includes within its scope the compounds of formula (I) or physiologically acceptable solvates thereof. , Including pharmaceutical compositions optionally mixed with one or more physiologically acceptable diluents or carriers.

  Further provided is a method for producing such a pharmaceutical composition comprising mixing the ingredients.

  The compounds of the invention can be formulated, for example, for oral, nasal, buccal, sublingual, parenteral, topical or rectal administration, particularly topical administration.

  Topical administration as used herein includes administration by insufflation and inhalation. Examples of various types of preparations for topical administration are used in ointments, lotions, creams, gels, foams, preparations for delivery by transdermal patches, powders, sprays, aerosols, inhalers or insufflators Capsules or cartridges or drops (eg eye drops or nasal drops) for spraying, solutions / suspensions for spraying, suppositories, pessaries, retention enemas, and chewing or licking tablets or pellets (for example after ulcers) For treatment) or liposomes or microencapsulated preparations.

  Ointments, creams and gels can be formulated, for example, using an aqueous or oily base and adding suitable thickeners and / or gelling agents and / or solvents. Thus, such bases can include, for example, water and / or oils such as fluidized barafin or vegetable oils such as peanut oil or rapeseed oil, or solvents such as polyethylene glycol. Thickeners and gelling agents that can be used depending on the nature of the base include soft paraffin, aluminum stearate, cetostearyl alcohol, polyethylene glycol, wool fat, beeswax, carboxypolymethylene and cellulose derivatives, and / or glyceryl monostearate And / or non-ionic emulsifiers.

  Lotions can be formed with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents and / or thickening agents.

  Powders for external application can be formed using any suitable powder base such as talc, lactose or starch. Drops can be formulated with an aqueous or non-aqueous base which also contains one or more dispersants, solubilizers, suspending agents or preservatives.

  Spray compositions can be formulated with a liquefied propellant, for example, as an aqueous solution or suspension, or as a pressurized pack, eg, an aerosol delivered from a metered dose inhaler. Aerosol compositions suitable for inhalation can be either suspensions or solutions, and compounds of formula (I) and suitable propellants such as fluorocarbons or hydrogen-containing chlorofluorocarbons or mixtures thereof, in particular hydrofluoroalkanes. In particular, it generally contains 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane or mixtures thereof, among others. Aerosol compositions can optionally contain additional formulation aids well known in the art, such as surfactants, such as oleic acid or lecithin, and a cosolvent, such as ethanol.

  Advantageously, the formulations of the present invention may be buffered by adding a suitable buffer.

  Capsules and cartridges, for example gelatin, containing the compound of the invention and a suitable powder base, such as lactose or starch, for use in an inhaler or insufflator can be formulated. Each capsule or cartridge may generally contain 20 μg to 10 mg of the compound of formula (I). Alternatively, the compounds of the present invention can be present without an excipient such as lactose.

  The proportion of active compound of formula (I) in the topical composition according to the invention depends on the exact type of formulation to be produced, but will generally be in the range from 0.001 to 10% by weight. In general, however, the proportions advantageously used for most types of preparations will be in the range of 0.005 to 1%, preferably 0.01 to 0.5%. However, the ratio used for powders for inhalation or insufflation will be in the range of 0.1-5%.

  The aerosol formulation is preferably adjusted so that the measured dose or “puff” of the aerosol contains 20 μg to 2000 μg, preferably about 20 μg to 500 μg of the compound of formula (I). Administration may be once daily or several times daily, for example 2, 3, 4 or 8 times, giving 1, 2 or 3 doses each time. The overall daily dose with an aerosol will be within the range 100 μg to 10 mg, preferably 200 μg to 2000 μg. The overall daily dose or metered dose delivered by capsules and cartridges in an inhaler or insufflator will generally be double that of an aerosol formulation.

  Topical preparations can be administered by application to the affected area one or more times per day; an occlusive dressing can be advantageously used over the skin area.

  For internal administration, the compounds according to the invention can be formulated in the usual ways, for example for oral, parenteral or rectal administration. Formulations for oral administration include syrups, elixirs, powders, granules, tablets and capsules, which are typically conventional auxiliaries such as binders, fillers, lubricants, disintegrants, wetting agents, suspensions. A turbidity agent, an emulsifier, a preservative, a buffer salt, a flavoring agent, a coloring agent and / or a sweetener are contained as necessary. However, dosage unit forms as described below are preferred.

  Preferred forms of preparation for internal administration are dosage unit forms, ie tablets and capsules. Such dosage unit forms contain 0.1 mg to 20 mg, preferably 2.5 to 10 mg, of a compound of the invention.

  The compounds according to the invention can generally be given by internal administration when systemic corticotherapy is indicated.

  In general terms, preparations for internal administration may contain 0.05-10% active ingredient depending on the type of preparation involved. The daily dose may vary from 0.1 mg to 60 mg, such as from 5 to 30 mg, depending on the condition being treated and the desired duration of treatment.

  Sustained release or enteric coated formulations may be advantageous, particularly for the treatment of inflammatory bowel disorders.

The compounds and pharmaceutical formulations according to the invention comprise one or more other therapeutic agents such as anti-inflammatory agents, anticholinergic agents (especially M ₁ / M ₂ / M ₃ receptor antagonists), β ₂ -adrenergic receptors It can be used in combination with or include those selected from body agonists, anti-infectives (eg antibiotics, antiviral agents) or antihistamines. Accordingly, the present invention, in another aspect, replaces a compound of formula (I) or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof with one or more other therapeutically active agents, such as With an anti-inflammatory agent (eg another corticosteroid or NSAID), an anticholinergic agent, a β ₂ -adrenergic receptor agonist, an anti-infective agent (eg antibiotic, antiviral agent) or an antihistamine A combination is provided. A compound of formula (I) or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof with a β ₂ -adrenergic receptor agonist and / or an anti-infective agent and / or a PDE-4 inhibitor; Combinations comprising together are preferred.

  If necessary, other therapeutic ingredients may be in the form of salts (eg as alkali metal or amine salts or acid addition salts) or in the form of prodrugs or as esters (eg lower alkyl esters) or solvates ( It will be apparent to those skilled in the art that the activity and / or stability and / or physical properties (eg, solubility) of the therapeutic ingredients can be optimized as, for example, hydrates.

Particularly preferred are combinations comprising a compound of the invention together with a β ₂ -adrenergic receptor agonist.

Examples of β ₂ -adrenergic receptor agonists include salmeterol (eg as a racemate or a single enantiomer, eg as R-enantiomer), salbutamol, formoterol, salmefamol, fenoterol or terbutaline and its salts, eg salmeterol xinafoic acid Salts, sulfates or free bases of salbutamol, or fumarate of formoterol. Long-acting β ₂ -adrenergic receptor agonists are preferred, particularly those with a therapeutic effect over 24 hours.

Other examples of β ₂ -adrenergic receptor agonists include carmoterol, etantherol, naminterol, clenbrelol, pyrbuterol, flerobuterol, reproterol, bambuterol, indacaterol and salts thereof.

Preferred β ₂ -adrenergic receptor agonists are WO 02/066422, WO 02/070490, WO 02/076933, WO 03/024439, WO 03/072539, WO 03/091204, WO 04/016578, WO 2004/022547. , WO 2004/037807, WO 2004/037773, WO 2004/037768, WO 2004/039762, WO 2004/039766, WO 01/42193 and WO 03/042160.

Particularly preferred β ₂ -adrenergic receptor agonists are compounds of formula (XX):

Or a salt or solvate thereof, wherein:
m is an integer from 2 to 8;
n is an integer from 3 to 11,
However, m + n is 5-19,
R ²¹ is —XSO ₂ NR ²⁶ R ²⁷ , wherein X is — (CH ₂ ) _p — or C _2-6 alkylene;
R ²⁶ and R ²⁷ are independently selected from hydrogen, C _1-6 alkyl, C _3-7 cycloalkyl, C (O) NR ²⁸ R ²⁹ , phenyl and phenyl (C _1-4 alkyl)-
Or R ²⁶ and R ²⁷ together with the nitrogen to which they are attached form a 5, 6 or 7 membered nitrogen-containing ring, and R ²⁶ and R ²⁷ are optionally halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, hydroxy substituted C _{1-6 ^{alkoxy, -CO 2 R 28, -SO 2}} NR 28 R 29, -CONR 28 R 29, -NR 28 C ( O) R ²⁹ , or substituted with 1 or 2 groups selected from 5, 6 or 7 membered heterocyclic ring;
R ²⁸ and R ²⁹ are independently selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, phenyl and phenyl (C _1-4 alkyl)-;
p is an integer of 0-6, preferably 0-4;
R ²² and R ²³ are independently selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy, halo, phenyl and C _1-6 haloalkyl; and
R ²⁴ and R ²⁵ are independently selected from hydrogen and C _1-4 alkyl, provided that the total number of carbon atoms in R ²⁴ and R ²⁵ is 4 or less.

Particularly preferred β ₂ -adrenergic receptor agonists include the following:
3- (4-{[6-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) hexyl] oxy} butyl) benzenesulfonamide;
3- (3-{[7-({(2R) -2-hydroxy-2- [4-hydroxy-3-hydroxymethyl) phenyl] ethyl} -amino) heptyl] oxy} propyl) benzenesulfonamide;
4-{(1R) -2-[(6- {2-[(2,6-dichlorobenzyl) oxy] ethoxy} hexyl) amino] -1-hydroxyethyl} -2- (hydroxymethyl) phenol l;
4-{(1R) -2-[(6- {4- [3- (cyclopentylsulfonyl) phenyl] butoxy} hexyl) amino] -1-hydroxyethyl} -2- (hydroxymethyl) phenol;
N- [2-hydroxyl-5-[(1R) -1-hydroxy-2-[[2-4-[[(2R) -2-hydroxy-2-phenylethyl] amino] phenyl] ethyl] amino] Ethyl] phenyl] formamide;
N-2 {2- [4- (3-phenyl-4-methoxyphenyl) aminophenyl] ethyl} -2-hydroxy-2- (8-hydroxy-2 (1H) -quinolinone-5-yl) ethylamine; and
5-[(R) -2- (2- {4- [4- (2-Amino-2-methyl-propoxy) -phenylamino] -phenyl} -ethylamino) -1-hydroxy-ethyl] -8- Hydroxy-1H-quinolin-2-one.

  Suitable anti-inflammatory agents include corticosteroids. Suitable corticosteroids that can be used in combination with the compounds of the present invention are oral and inhaled corticosteroids or their prodrugs with anti-inflammatory activity. Examples are methylprezonidolone, prezonidolone, fluticasone propionate, 6α, 9α-difluoro-11β-hydroxy-16α-methyl-17α-[(4-methyl-1,3-thiazole-5-carbonyl) oxy]- 3-oxo-androst-1,4-diene-17β-carbothioic acid S-fluoromethyl ester, fluoromethyl ester, 6α, 9α-difluoro-17α-[(2-furanylcarbonyl) oxy] -11β-hydroxy- 16α-Methyl-3-oxo-androsta-1,4-diene-17β-carbothioic acid S-fluoromethyl ester, 6α, 9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy- Androsta-1,4-diene-17β-carbothioic acid S- (2-oxo-tetrahydro-furan-3S-yl) ester, beclomethasone ester (eg 17-propionic acid ester or 17,21-dipropionic acid ester), Budesonide, funizolide, Momestazone ester (eg furoate), triamcinolone acetonide, rofleponide, ciclezonide (16α, 17-[[(R) -cyclohexylmethylene] bis (oxy)]-11β, 21-dihydroxy-pregna-1,4- Diene-3,20-dione), butyxocortopropionate, RPR-106541 and ST-126. A preferred corticosteroid is fluticasone propionate, 6α, 9α-difluoro-11β-hydroxy-16α-methyl-17α-[(4-methyl-1,3-thiazole-5-carbonyl) oxy] -3-oxo- Androsta-1,4-diene-17β-carbothioic acid S-fluoromethyester and 6α, 9α-difluoro-17α-[(2-furanylcarbonyl) oxy] -11β-hydroxy-16α-methyl-3-oxo- Androsta-1,4-diene-17β-carbothioic acid S-fluoromethyl ester, more preferably 6α, 9α-difluoro-17α-[(2-furanylcarbonyl) oxy] -11β-hydroxy-16α-methyl-3 -Oxo-androst-1,4-diene-17β-carbothioic acid S-fluoromethyl ester. Further examples of corticosteroids are 6α, 9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α- (2,2,3,3-tetramethylcyclopropylcarbonyl) oxy-androst-1 , 4-Diene-17β-carbothioic acid S-cyanomethyl ester and 6α, 9α-difluoro-11β-hydroxy-16α-methyl-17α- (1-methylcyclopropylcarbonyl) oxy-3-oxo-androst-1, Includes 4-diene-17β-carbothioic acid S-fluoromethyl ester.

  Non-steroidal compounds with glucocorticoid agonists that may have selectivity for transcriptional repression over transcriptional activation and may be useful in combination therapy include those protected by the following patents : WO 03/082827, WO 01/10143, WO98 / 54159, WO 04/005229, WO 04/009016, WO 04/009017, WO 04/018429, WO 03/104195, WO 03/082787, WO 03/082280, WO 03/059899, WO 03/101932, WO 02/02565, WO 01/16128, WO 00/66590, WO 03/086294, WO 04/026248, WO 03/061651, WO 03/08277.

  Suitable anti-inflammatory agents include non-steroidal anti-inflammatory agents (NSAIDs).

Suitable NSAIDs include sodium cromoglycate, nedocromil sodium, phosphodiesterase (PDE) inhibitors (eg, theophylline, PDE4 inhibitors or mixed PDE3 / PDE4 inhibitors), leukotriene antagonists, inhibitors of leukotriene synthesis (eg, montelukast), iNOS inhibitors, tryptase and elastase inhibitors, beta-2 integrin antagonists and adenosine receptor agonists or antagonists (eg adenosine 2a agonists), cytokine antagonists (eg chemokine antagonists such as CCR3 antagonists) or cytokine synthesis Or 5-lipoxygenase inhibitors. Other suitable β ₂ -adrenergic receptor agonists are salmeterol (eg as xinafoate), salbutamol (eg as sulfate or free base), formoterol (eg as fumarate), fenoterol or terbutaline and its salts Is included. iNOS (inducible nitric oxide synthase inhibitor) is preferred for oral administration. Suitable iNOS inhibitors include those disclosed in WO 93/13055, WO 98/30537, WO 02/50021, WO95 / 34534 and WO99 / 62875. Suitable CCR3 inhibitors include those disclosed in WO02 / 26722.

  Of particular interest is the use of compounds of formula (I) in combination with phosphodiesterase 4 (PDE4) inhibitors, especially in the case of formulations adapted for inhalation. A PDE4-specific inhibitor useful in this aspect of the invention may be any compound known to inhibit PDE4 appeal or found to act as a PDE4 inhibitor, which is PDE4 It is only an inhibitor, not a compound that inhibits other members of the PDE family, such as PED3 and PDE5, and PDE4.

  Interesting compounds are cis-4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-1-carboxylic acid, 2-carbomethoxy-4-cyano-4- (3-cyclopropylmethoxy-4- Difluoromethoxyphenyl) cyclohexane-1-one and cis- [4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexane-1-ol]. Also, cis-4-cyano-4- [3- (cyclopentyloxy) -4-methoxyphenyl] cyclohexane-1-carboxylic acid (also known as silomilast) described in US Pat. No. 5,552,438 issued on September 3, 1996. And the salts, esters, prodrugs or physical forms thereof; this patent and the compounds it discloses are hereby incorporated by reference in their entirety.

  Other compounds of interest are AWD-12-281 from Elbion (Hofgen, N. et al. 15th EFMC Int Symp Med Chem (Sept 6-10, Edinburgh) 1998, Abst P. 98; CAS reference number 247584020-9) A 9-benzyladenine derivative (INSERM) named NCS-613; D-4418 from Chiroscience and Schering-Plough; a benzodiazepine PDE4 inhibitor named CI-1018 (PD-168787) and Pfizer; Benzodiazepine PDE4 inhibitors identified by Kyowa Hakko and disclosed in WO 99/16766; K-34 from Kyowa Hakko; V-11294A from Napp (Landells, LJ et al. Eur Resp J [Annu Cong Eur Resp Soc (Sept 19-23, Geneva) 1998] 1998, 12 (Suppl. 28): Abst P2393); Roflumilast from Byk-Gulden (CAS reference number 162401-32-3) and phthalazinone (WO99 / 47505, see disclosure thereof) Pumafenthrin, (-)-p-[(4aR *, 10bS *)-9-ethoxy-1,2,3,4,4a, 10b-hexahydro-8-methoxy-2- Methylbenzo [c] [1,6] naphthyridin-6-yl] -N, N-diisopropylbenzamide, which is a mixed PDE3 / PDE4 inhibitor manufactured and published by Byk-Gulden, now Altana; Almirall- Allophylline under development by Prodesfarma; VM554 / UM565 from Vernalis; or T-440 (Tanabe Seiyaku; Fuji, K. et al. J Pharmacol Exp Ther, 1998, 284 (1): 162), and T2585.

  Further interesting compounds are disclosed in the published international patent applications WO04 / 024728 (Glaxo Group Ltd), PCT / EP2003 / 014867 (Glaxo Group Ltd) and PCT / EP2004 / 005494 (Glaxo Group Ltd).

Suitable anticholinergic agents are those compounds that act as antagonists at the muscarinic receptors, in particular antagonists of M ₁ or M ₃ receptors, M ₁ / M ₃ or M ₂ / M ₃ receptor dual antagonist or It is a compound that is a total antagonist of M ₁ / M ₂ / M ₃ receptors. Exemplary compounds for administration by inhalation are ipratropium (eg, bromide, CAS 22254-24-6, sold under the name Atrovent), oxitropium (eg, bromide, CAS 30286-75-0) And tiotropium (for example, CAS 136310-93-5, sold as bromide, sold under the name Spiriva). Equally interesting are levatropate (eg as hydrobromide, CAS 262586-79-8) and LAS-34273 disclosed in WO 01/04118. Exemplary compounds for oral administration include pirenzepine (CAS 28797-61-7), darifenacin (CAS 133099-04-4, or CAS 133099-07 for hydrobromide sold under the name Enablex -7), oxybutynin (CAS 5633-20-5, sold under the name Ditropan), terodiline (CAS 15793-40-5), tolterodine (CAS 124937-51-5, or CAS 124937- for tartrate) 52-6, sold under the name Detrol), otirolium (for example, as bromide, CAS 26095-59-0, sold under the name Spasmomen), trospium chloride (CAS 10405-02-4) and solifenacin ( CAS 242478-37-1 or succinate also known as YM-905 and sold under the name Vesicare includes CAS 242478-38-2).

Other suitable anticholinergic agents include compounds of formula (XXI) disclosed in US patent application 60/487981:

Where the preferred configuration of the alkyl chain attached to the tropane ring is the end;
R ³¹ and R ³² are independently preferably a linear or branched lower alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 5 to 6 carbon atoms, 6 to 10 A cycloalkyl-alkyl group having 2 carbon atoms, 2-thienyl, 2-pyridyl, phenyl, phenyl substituted with an alkyl group having 4 or fewer carbon atoms and an alkoxy group having 4 or fewer carbon atoms Selected from the group consisting of phenyl;
X ^- represents an anion which is involved in the positive charge of the N atom. X ⁻ may be chloride, bromide, iodide, sulfate, benzenesulfonate and toluenesulfonate, but is not limited to
Examples include:
(3-endo) -3- (2,2-di-2-thienylethenyl) -8,8-dimethyl-8-azoniabicyclo [3.2.1] octane bromide;
(3-endo) -3- (2,2-diphenylethenyl) -8,8-dimethyl-8-azoniabicyclo [3.2.1] octane bromide;
(3-endo) -3- (2,2-diphenylethenyl) -8,8-dimethyl-8-azoniabicyclo [3.2.1] octane 4-methylbenzenesulfonate;
(3-endo) -8,8-dimethyl-3- [2-phenyl-2- (2-thienyl) ethenyl] -8-azoniabicyclo [3.2.1] octane bromide; and / or
(3-Endo) -8,8-dimethyl-3- [2-phenyl-2- (2-pyridinyl) ethenyl] -8-azoniabicyclo [3.2.1] octane bromide.

Further suitable anticholinergic agents include compounds of formula (XXII) or (XXIII) disclosed in US patent application 60/511009:

In the formula:
The indicated H atom is in the exo position;
R ⁴¹ represents an anion involved in the positive charge of the N atom. R ⁴¹ may be, but is not limited to, chloride, bromide, iodide, sulfate, benzenesulfonate and toluenesulfonate;
R ⁴² and R ⁴³ are independently a linear or branched lower alkyl group (preferably having 1 to 6 carbon atoms), a cycloalkyl group (having 5 to 6 carbon atoms), Cycloalkyl-alkyl groups (having 6 to 10 carbon atoms), heterocycloalkyl (having 5 or 6 carbon atoms and N or O as a heteroatom), heterocycloalkyl-alkyl (6 to 10 carbon atoms) Selected from the group consisting of carbon atoms and N or O as a heteroatom), aryl, optionally substituted aryl, heteroaryl and optionally substituted heteroaryl;
R ⁴⁴ is (C ₁ -C ₆ ) alkyl, (C ₃ -C ₁₂ ) cycloalkyl, (C ₃ -C ₇ ) heterocycloalkyl, (C ₁ -C ₆ ) alkyl (C ₃ -C ₁₂ ) cycloalkyl , (C ₁ -C ₆ ) alkyl (C ₃ -C ₇ ) heterocycloalkyl, aryl, heteroaryl, (C ₁ -C ₆ ) alkyl-aryl, (C ₁ -C ₆ ) alkyl-heteroaryl, -OR ⁴⁵ , -CH ₂ OR ⁴⁵ , -CH ₂ OH, -CN, -CF ₃ , -CH ₂ O (CO) R ⁴⁶ , -CO ₂ R ⁴⁷ , -CH ₂ NH ₂ , -CH ₂ N (R ⁴⁷ ) SO ₂ R ⁴⁵ , -SO ₂ N (R ⁴⁷ ) (R ⁴⁸ ), -CON (R ⁴⁷ ) (R ⁴⁸ ), -CH ₂ N (R ⁴⁸ ) CO (R ⁴⁶ ), -CH ₂ N (R ⁴⁸ ) SO ₂ (R ⁴⁶ ), —CH ₂ N (R ⁴⁸ ) CO ₂ (R ⁴⁵ ), —CH ₂ N (R ⁴⁸ ) CONH (R ⁴⁷ );
R ⁴⁵ is (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkyl (C ₃ -C ₁₂ ) cycloalkyl, (C ₁ -C ₆ ) alkyl (C ₃ -C ₇ ) heterocycloalkyl, C ₁ -C ₆₎ alkyl - aryl, (C ₁ -C ₆₎ alkyl - is selected from the group consisting of heteroaryl;
R ⁴⁶ is (C ₁ -C ₆ ) alkyl, (C ₃ -C ₁₂ ) cycloalkyl, (C ₃ -C ₇ ) heterocycloalkyl, (C ₁ -C ₆ ) alkyl (C ₃ -C ₁₂ ) cycloalkyl , (C ₁ -C ₆ ) alkyl (C ₃ -C ₇ ) heterocycloalkyl, aryl, heteroaryl, (C ₁ -C ₆ ) alkyl-aryl, (C ₁ -C ₆ ) alkyl-heteroaryl Selected from;
R ⁴⁷ and R ⁴⁸ are independently H, (C ₁ -C ₆ ) alkyl, (C ₃ -C ₁₂ ) cycloalkyl, (C ₃ -C ₇ ) heterocycloalkyl, (C ₁ -C ₆ ) alkyl. (C ₃ -C ₁₂ ) cycloalkyl, (C ₁ -C ₆ ) alkyl (C ₃ -C ₇ ) heterocycloalkyl, (C ₁ -C ₆ ) alkyl-aryl, and (C ₁ -C ₆ ) alkyl- Selected from the group consisting of heteroaryl, including for example:
(Endo) -3- (2-methoxy-2,2-di-thiophen-2-yl-ethyl) -8,8-dimethyl-8-azonia-bicyclo [3.2.1] octane iodide;
3-((endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propionitrile;
(Endo) -8-methyl-3- (2,2,2-triphenyl-ethyl) -8-aza-bicyclo [3.2.1] octane;
3-((endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propionamide;
3-((endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propionic acid;
(Endo) -3- (2-cyano-2,2-diphenyl-ethyl) -8,8-dimethyl-8-azonia-bicyclo [3.2.1] octane iodide;
(Endo) -3- (2-cyano-2,2-diphenyl-ethyl) -8,8-dimethyl-8-azonia-bicyclo [3.2.1] octane bromide;
3-((endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propan-1-ol;
N-benzyl-3-((endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propionamide;
(Endo) -3- (2-carbamoyl-2,2-diphenyl-ethyl) -8,8-dimethyl-8-azonia-bicyclo [3.2.1] octane iodide;
1-benzyl-3- [3-((endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propyl] -urea;
1-ethyl-3- [3-((endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propyl] -urea;
N- [3-((endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propyl] -acetamide;
N- [3-((endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propyl] -benzamide;
3-((endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-di-thiophen-2-yl-propiononitrile;
(Endo) -3- (2-cyano-2,2-di-thiophen-2-yl-ethyl) -8,8-dimethyl-8-azonia-bicyclo [3.2.1] octane iodide;
N- [3-((endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propyl] -benzenesulfonamide;
[3-((endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propyl] -urea;
N- [3-((endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propyl] -methanesulfonamide; and / or
(Endo) -3- {2,2-diphenyl-3-[(1-phenyl-methanoyl) -amino] -propyl} -8,8-dimethyl-8-azonia-bicyclo [3.2.1] octane bromide.

More preferred compounds useful according to the invention include:
(Endo) -3- (2-methoxy-2,2-di-thiophen-2-yl-ethyl) -8,8-dimethyl-8-azonia-bicyclo [3.2.1] octane iodide;
(Endo) -3- (2-cyano-2,2-diphenyl-ethyl) -8,8-dimethyl-8-azonia-bicyclo [3.2.1] octane iodide;
(Endo) -3- (2-cyano-2,2-diphenyl-ethyl) -8,8-dimethyl-8-azonia-bicyclo [3.2.1] octane bromide;
(Endo) -3- (2-carbamoyl-2,2-diphenyl-ethyl) -8,8-dimethyl-8-azonia-bicyclo [3.2.1] octane iodide;
(Endo) -3- (2-cyano-2,2-di-thiophen-2-yl-ethyl) -8,8-dimethyl-8-azonia-bicyclo [3.2.1] octane iodide; and / or
(Endo) -3- {2,2-diphe-3-[(1-phenyl-methanoyl) -amino] -propyl} -8,8-dimethyl-8-azonia-bicyclo [3.2.1] octane bromide.

  Suitable antihistamines (also called H1 receptor antagonists) include one or more of a number of antagonists that inhibit H1 receptors and are known to be safe for human use. First generation antagonists include derivatives of ethanolamine, ethylenediamine and alkylamines such as diphenylhydramine, pyrylamine, clemastine, chlorophenylamine. Non-sedating second generation antagonists include iolatidine, desloratidine, terfenadine, astemizole, acribastine, azelastine, levocetirizine, fexofenadine and cetirizine.

  Examples of preferred antihistamines include loratidine, desloratidine, fexofenadine and cetirizine.

  Accordingly, the present invention, in another embodiment, comprises a combination comprising a compound of formula (I), a pharmaceutically acceptable salt, solvate or physiologically acceptable functional derivative thereof together with a PDE4 inhibitor. provide.

Accordingly, the present invention, in another aspect, combines a compound of formula (I), a pharmaceutically acceptable salt, solvate or physiologically acceptable functional derivative thereof with a β ₂ -adrenergic receptor agonist. Provide combinations including together.

  Accordingly, the present invention, in another aspect, comprises a combination comprising a compound of formula (I), a pharmaceutically acceptable salt, solvate or physiologically acceptable functional derivative thereof together with an anticholinergic agent. provide.

  The invention thus provides, in another aspect, a combination comprising a compound of formula (I), a pharmaceutically acceptable salt, solvate or physiologically acceptable functional derivative thereof together with an antihistamine. .

Accordingly, the present invention in another aspect provides a compound of formula (I), a pharmaceutically acceptable salt, solvate or physiologically acceptable functional derivative thereof, comprising a PDE4 inhibitor and a β ₂ -adrenergic receptor. A combination comprising with a body agonist is provided.

  Accordingly, the present invention provides, in another embodiment, a compound of formula (I), a pharmaceutically acceptable salt, solvate or physiologically acceptable functional derivative thereof as an anticholinergic agent and a PDE-4 inhibitor. Provide combinations including with.

  The above combinations can be conveniently presented for use in the form of pharmaceutical preparations. Accordingly, a pharmaceutical formulation comprising the above combination together with a pharmaceutically acceptable diluent or carrier represents another aspect of the present invention.

  The individual compounds in such combinations can be administered either individually or in combination, in a pharmaceutical formulation, either sequentially or simultaneously. Preferably, the individual compounds s of such combinations can be administered simultaneously in a combined pharmaceutical combination. Appropriate doses of known therapeutic agents will be readily appreciated by those skilled in the art.

  The compound of formula (I) and solvates thereof can be prepared by the following method which constitutes another embodiment of the present invention.

The process according to the invention for producing the compound of formula (I) comprises a carboxylic acid of formula (II)

は上記で定義した通りである）を式 L-CH₂-CN の化合物（式中、L は脱離基を示す）と反応させることを含む。 (Wherein R ₁ , R ₂ , R ₃ , R ₄ and

Is as defined above) with a compound of formula L—CH ₂ —CN wherein L is a leaving group.

In this method, a compound of formula (II) is prepared under standard conditions with a compound of formula L-CH ₂ -CN (wherein L represents a leaving group such as a halogen atom, tosyl or mesyl group). Can be reacted. For example, this reaction can be carried out in an inert polar organic solvent such as N, N-dimethylformamide in the presence of a base such as potassium carbonate or sodium carbonate.

  The compounds of formula (II) can conveniently be employed as salts (if such salts can be prepared in crystalline form) or as solvates.

In another embodiment of this invention the compound of formula (II)

は式(I)の化合物のために定義した通りである）が提供される。 (Wherein R ₁ , R ₂ , R ₃ , R ₄ and

Is as defined for compounds of formula (I).

Compounds of formula L—CH ₂ —CN are known or can be prepared by known methods.

The compound of formula (II) has a corresponding 17α-hydroxyl derivative of formula (III):

は上記で定義した通りである）から、
例えば、G. H. Phillipps et al. により記載された17αカルボン酸エステルの製造方法 (Journal of Medicinal Chemistry, (1994), 37, 3717-3729) 及び Druzgala et al. により記載された 17α炭酸エステルロテプレドノールエタボネートの製造方法 (Journal of Steroid Chemistry and Molecular Biology, (1991), 38, 149-154) と同様の方法を用いて製造することができる。この段階は、典型的には、中塩基、例えばトリエチルアミンの存在下に、好適な溶剤、例えばジクロロメタン中で、ヒドロキシ酸(III) とクロロホルメート R₁OCOCl、又は無水物 (R₁OCO)₂O とを反応させることを含む。立体的に妨害された R₁ の場合には、無水物 (R₁OCO)₂O がクロロホルメートよりも好ましいことがある。 (Wherein R ₂ , R ₃ , R ₄ and

Is as defined above)
For example, the method for producing 17α carboxylic acid ester described by GH Phillipps et al. (Journal of Medicinal Chemistry, (1994), 37, 3717-3729) and 17α carbonic acid ester loteprednol It can be produced using a method similar to the production method of Bonate (Journal of Steroid Chemistry and Molecular Biology, (1991), 38, 149-154). This step is typically carried out in the presence of a medium base, such as triethylamine, in a suitable solvent, such as dichloromethane, with hydroxy acid (III) and chloroformate R ₁ OCOCl, or anhydride (R ₁ OCO) ₂ Reacting with O 2. In the case of sterically hindered R ₁ , the anhydride (R ₁ OCO) ₂ O may be preferred over chloroformate.

In general, the chloroformate or anhydride will be employed in at least twice the molar amount relative to the compound of formula (III). The second mole of chloroformate or anhydride tends to react with the carboxylic acid moiety of the compound of formula (III) and will need to be removed by reaction with an amine such as diethylamine or 1-methylpiperazine. . Chloroformates are commercially available or can be reacted by standard methods such as the corresponding alcohol R ₁ OH and phosgene, more preferably triphosgene, in the presence of a base such as pyridine in a suitable solvent such as dichloromethane. By making it, it can manufacture easily. More conveniently, reacting 17α-hydroxy derivative (III) with chloroformate R ₁ OCOCl or anhydride (R ₁ OCO) ₂ O in pyridine solution often gives 17α carbonate (II) directly .

  Compounds of formula (III) are known or can be prepared by the procedure described by G. H. Phillipps et al. In Journal of Medicinal Chemistry, (1994), 37, 3717-3729.

The following compounds of formula (II) are novel and form one aspect of the present invention:
(6α, 11β, 16α, 17α) -17-({[(1,1-dimethylethyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost- 1,4-diene-17-carboxylic acid;
(6α, 11β, 16α, 17α) -17-({[(1,1-dimethylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost- 1,4-diene-17-carboxylic acid;
(6α, 11β, 16α, 17α) -17-({[(1-Ethylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost-1, 4-diene-17-carboxylic acid;
(6α, 11β, 16α, 17α) -6,9-Difluoro-11-hydroxy-16-methyl-17-[({[2-methyl-1- (1-methylethyl) propyl] oxy} carbonyl) oxy] -3-oxoandrosta-1,4-diene-17-carboxylic acid;
(6α, 11β, 16α, 17α) -17-({[(2-Ethylbutyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost-1,4 -Diene-17-carboxylic acid;
(6α, 11β, 16α, 17α) -17-({[(2,2-dimethylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost- 1,4-diene-17-carboxylic acid;
(6α, 11β, 16α, 17α) -17-({[(1-Ethyl-2-methylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandro Sta-1,4-diene-17-carboxylic acid;
(6α, 11β, 16α, 17α) -17-({[(1,2-dimethylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost- 1,4-diene-17-carboxylic acid;
(6α, 11β, 16α, 17α) -17-{[(Cyclopentyloxy) carbonyl] oxy} -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost-1,4-diene-17 -carboxylic acid;
(6α, 11β, 16α, 17α) -6,9-Difluoro-11-hydroxy-16-methyl-17-[({[(1SR, 2RS) -2-methylcyclohexyl] oxy} carbonyl) oxy] -3- Oxoandrosta-1,4-diene-17-carboxylic acid;
(6α, 11β, 16α, 17α) -6,9-Difluoro-11-hydroxy-16-methyl-17-[({[4- (1-methylethyl) cyclohexyl] oxy} carbonyl) oxy] -3-oxo Androsta-1,4-diene-17-carboxylic acid;
(6α, 11β, 16α, 17α) -17-({[(1RS, 2RS, 4SR) -bicyclo [2.2.1] hept-2-yloxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy- 16-methyl-3-oxoandrosta-1,4-diene-17-carboxylic acid; and
(6α, 11β, 16α, 17α) -17-({[(1RS, 2SR, 4SR) -bicyclo [2.2.1] hept-2-yloxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy- 16-methyl-3-oxoandrosta-1,4-diene-17-carboxylic acid.

  The following compounds of formula (II) are also novel and form an aspect of the present invention.

(6α, 11β, 16α, 17α) -6,9-Difluoro-11-hydroxy-16-methyl-3-oxo-17-[({[(1S, 2R, 4S) -1,7,7-trimethylbicyclo [2.2.1] hept-2-yl] oxy} carbonyl) oxy] androsta-1,4-diene-17-carboxylic acid;
(6α, 11β, 16α, 17α) -6,9-Difluoro-11-hydroxy-16-methyl-3-oxo-17-[({[(1R, 2S, 4R) -1,7,7-trimethylbicyclo [2.2.1] hept-2-yl] oxy} carbonyl) oxy] androsta-1,4-diene-17-carboxylic acid;
(6α, 11β, 16α, 17α) -6,9-Difluoro-11-hydroxy-16-methyl-3-oxo-17-[({[(1R, 2R, 3R, 5S) -2,6,6- Trimethylbicyclo [3.1.1] hept-3-yl] oxy} carbonyl) oxy] androsta-1,4-diene-17-carboxylic acid;
(6α, 11β, 16α, 17α) -6,9-Difluoro-11-hydroxy-16-methyl-3-oxo-17-[({[(1S, 2S, 3S, 5R) -2,6,6- Trimethylbicyclo [3.1.1] hept-3-yl] oxy} carbonyl) oxy] androsta-1,4-diene-17-carboxylic acid;
(6α, 11β, 16α, 17α) -6,9-Difluoro-11-hydroxy-16-methyl-3-oxo-17-[({[(1R, 2R, 4S) -1,3,3-trimethylbicyclo [2.2.1] hept-2-yl] oxy} carbonyl) oxy] androsta-1,4-diene-17-carboxylic acid;
(6α, 11β, 16α, 17α) -17-({[(trans-4-ethylcyclohexyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost- 1,4-diene-17-carboxylic acid;
(6α, 11β, 16α, 17α) -17-({[(cis-4-ethylcyclohexyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost- 1,4-diene-17-carboxylic acid;
(6α, 11β, 16α, 17α) -6,9-Difluoro-11-hydroxy-16-methyl-3-oxo-17-({[(1-propylbutyl) oxy] carbonyl} oxy) androsta-1, 4-diene-17-carboxylic acid;
(6α, 11β, 16α, 17α) -6,9-Difluoro-11-hydroxy-16-methyl-3-oxo-17-[({[(1RS, 2RS, 4RS) -1,7,7-trimethylbicyclo [2.2.1] hept-2-yl] oxy} carbonyl) oxy] androsta-1,4-diene-17-carboxylic acid;
(6α, 11β, 16α, 17α) -6,9-Difluoro-11-hydroxy-16-methyl-3-oxo-17-({[(1,2,2-trimethylpropyl) oxy] carbonyl} oxy) andro Sta-1,4-diene-17-carboxylic acid; and
(6α, 11β, 16α, 17α) -6,9-Difluoro-11-hydroxy-16-methyl-17-[({[1- (1-methylethyl) butyl] oxy} carbonyl) oxy] -3-oxo Androsta-1,4-diene-17-carboxylic acid.

  The compounds of formula (I) and / or their solvates exhibit an agonistic action at the glucocorticoid receptor.

  The compounds of formula (I) and / or their solvates exhibit good anti-inflammatory properties and have predictable pharmacokinetic and pharmacodynamic behavior. They are also attractive due to, for example, increased selectivity for glucocorticoid receptors over progesterone receptors and / or increased selectivity for glucocorticoid receptor-mediated transcriptional repression over transcriptional activation. May have a side effect profile.

  The inclusion is illustrated by the following non-limiting examples:

General chromatographic purification was performed using Bond Elut silica gel cartridges commercially available from Varian. These cartridges were preconditioned with dichloromethane prior to use. LCMS was performed on a Supelcosil LCABZ + PLUS column (3.3 cm x 4.6 mm ID), 0.1% HCO ₂ H and 0.01 M ammonium acetate (solvent A) in water, and 0.05% HCO ₂ H and 5% water in acetonitrile ( Elution with solvent B) using the following elution gradient: 0-0.7 min 0% B, 0.7-4.2 min 100% B, 4.2-5.3 min 0% B, 5.3-5.5 min 0 ml flow at 0 ml % B. Mass spectra were recorded on a Fisons VG Platformf spectrometer using electrospray positive and negative modes (ES + ve and ES-ve).

  Automated preparative HPLC was performed using a Waters 600 gradient pump, Waters 2767 injection / collector, Waters Reagent Manager, Micromass ZMD mass spectrometer, Gilson Aspec waste collector and Gilson 115 post-fraction UV detector. The column used was typically a Supelco LCABZ ++ column with dimensions of 20 mm ID x 100 mm length. The stationary phase particle size is 5μm. The flow rate was 20 ml / min and the run time was 15 minutes, which included a 10 minute gradient followed by a 5 minute column flush and re-equilibration step.

  Solvent A: aqueous solvent = water + 0.1% formic acid.

  Solvent B: Organic solvent = MeCN: Water 95: 5 + 0.05% Formic acid.

  The specific gradient used was dependent on the retention time of the analytical system. 5-30% B for 2.0-2.8 minutes, 15-55% B for 2.5-3.0 minutes, 30-80% B for 2.8-4.0 minutes and 50-90% B for 3.8-5.5 minutes.

Intermediate examples
Intermediate 1: (6α, 11β, 16α, 17α) -17-({[(1,1-dimethylethyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3- Oxoandrosta-1,4-diene-17-carboxylic acid

Bis (1,1-dimethylethyl) carbonate (121 mg, 0.56 mmol) was added to (6α, 11β, 16α, 17α) -6,9-difluoro-11,17-dihydroxy-16-methyl- in pyridine (5 ml). Add this to a stirred solution of 3-oxoandrost-1,4-diene-17-carboxylic acid (GH Phillipps et al., (1994) Journal of Medicinal Chemistry, 37, 3717-3729) (200 mg, 0.5 mmol). The mixture was stirred overnight at room temperature. The solvent was evaporated and the residue was stirred with 2M hydrochloric acid (20ml) and the resulting precipitate was collected by filtration, washed with water and dried in vacuo at 60 ° C to give the title compound : LCMS retention time 3.27min.

Intermediate 2: (6α, 11β, 16α, 17α) -17-({[(1,1-dimethylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3- Oxoandrosta-1,4-diene-17-carboxylic acid

From bis (1,1-dimethylpropyl) dicarbonate, (6α, 11β, 16α, 17α) -17-({[(1,1-dimethylethyl) oxy] carbonyl} oxy) -6,9-difluoro-11- Prepared using a method similar to that described for hydroxy-16-methyl-3-oxoandrost-1,4-diene-17-carboxylic acid ( Intermediate 1 ). LCMS retention time 3.38 minutes.

Intermediate 3: (6α, 11β, 16α, 17α) -17-({[(1-ethylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandro Sta-1,4-diene-17-carboxylic acid

A solution of 3-pentanol (108 μl, 1 mmol) and pyridine (81 μl, 1 mmol) in anhydrous dichloromethane (2 ml) was stirred with triphosgene (98 mg, 0.33 mmol) and anhydrous (ice) in anhydrous dichloromethane (4 ml). Was added in portions over 10 minutes under nitrogen. After 1 hour, about half of the resulting chloroformate solution was dissolved in (6α, 11β, 16α, 17α) -6,9-difluoro-11,17-dihydroxy-16-methyl-3-oxo in pyridine (2 ml). To a solution of androsta-1,4-diene-17-carboxylic acid (200 mg, 0.5 mmol) was added and the mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was stirred with 2M hydrochloric acid (10ml) and the resulting precipitate was collected by filtration, washed with water and dried in vacuo to give the title compound as a white solid (246mg): LCMS retention time 3.42 Minutes.

Intermediate 4: (6α, 11β, 16α, 17α) -6,9-difluoro-11-hydroxy-16-methyl-17-[({[2-methyl-1- (1-methylethyl) propyl] oxy} Carbonyl) oxy] -3-oxoandrost-1,4-diene-17-carboxylic acid

From 2,4-dimethyl-3-pentanol, (6α, 11β, 16α, 17α) -17-({[(1-ethylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy- Prepared using a method similar to that described for 16-methyl-3-oxoandrosta-1,4-diene-17-carboxylic acid ( Intermediate 3 ). LCMS retention time 3.58 minutes.

Intermediate 5: (6α, 11β, 16α, 17α) -17-({[(2-ethylbutyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrosta 1,4-diene-17-carboxylic acid

From 2-ethyl-1-butanol, (6α, 11β, 16α, 17α) -17-({[(1-ethylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl Prepared using a method similar to that described for -3-oxoandrost-1,4-diene-17-carboxylic acid ( Intermediate 3 ). LCMS retention time 3.63 minutes.

Intermediate 6: (6α, 11β, 16α, 17α) -17-({[(2,2-dimethylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3- Oxoandrosta-1,4-diene-17-carboxylic acid

From 2,2-dimethyl-1-propanol, (6α, 11β, 16α, 17α) -17-({[(1-ethylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16 Prepared using a method similar to that described for -methyl-3-oxoandrosta-1,4-diene-17-carboxylic acid ( Intermediate 3 ). LCMS retention time 3.47 minutes.

Intermediate 7: (6α, 11β, 16α, 17α) -17-({[(1-ethyl-2-methylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl- 3-oxoandrosta-1,4-diene-17-carboxylic acid

From 2-methyl-3-pentanol, (6α, 11β, 16α, 17α) -17-({[(1-ethylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16- Prepared using a method similar to that described for methyl-3-oxoandrost-1,4-diene-17-carboxylic acid ( Intermediate 3 ). LCMS retention time 3.54 minutes.

Intermediate 8: (6α, 11β, 16α, 17α) -17-({[(1,2-dimethylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3- Oxoandrosta-1,4-diene-17-carboxylic acid

From 3-methyl-2-butanol, (6α, 11β, 16α, 17α) -17-({[(1-ethylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl Prepared using a method similar to that described for -3-oxoandrost-1,4-diene-17-carboxylic acid ( Intermediate 3 ). LCMS retention time 3.43 minutes.

Intermediate 9: (6α, 11β, 16α, 17α) -17-{[(Cyclopentyloxy) carbonyl] oxy} -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost-1,4 -Diene-17-carboxylic acid

A solution of cyclopentyl chloroformate (268 mg, 1.8 mmol) in dry dichloromethane (2 ml) was added to (6α, 11β, 16α, 17α) -6,9-difluoro-11,17-dihydroxy- in dry dichloromethane (5 ml). To a stirred and (ice) cooled solution of 16-methyl-3-oxoandrost-1,4-diene-17-carboxylic acid (298 mg, 0.75 mmol) and triethylamine (0.21 ml, 1.5 mmol) was added the mixture. Stir in ice for 2 hours and overnight at room temperature. The mixture was washed sequentially with aqueous sodium bicarbonate, 1M hydrochloric acid and water (30 ml each), then dried through a hydrophobic frit and evaporated. The residue was dissolved in 1,4-dioxane (10 ml) and treated with N-methylpiperazine (200 mg, 2 mmol) and the mixture was stirred at room temperature until LCMS indicated that the reaction was complete. The mixture was added in portions to stirred and (ice) cooled 2M hydrochloric acid and the precipitated product was collected, washed with water and dried in vacuo to give the title compound (31 mg): LCMS retention time 3.36 min.

Intermediate 10: (6α, 11β, 16α, 17α) -6,9-difluoro-11-hydroxy-16-methyl-17-[({[(1SR, 2RS) -2-methylcyclohexyl] oxy} carbonyl) oxy ] -3-Oxoandrosta-1,4-diene-17-carboxylic acid

From racemic cis-2-methylcyclohexanol, (6α, 11β, 16α, 17α) -17-({[(1-ethylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16 Prepared using a method similar to that described for -methyl-3-oxoandrosta-1,4-diene-17-carboxylic acid ( Intermediate 3 ). LCMS retention time 3.62 minutes.

Intermediate 11: (6α, 11β, 16α, 17α) -6,9-difluoro-11-hydroxy-16-methyl-17-[({[4- (1-methylethyl) cyclohexyl] oxy} carbonyl) oxy] -3-oxoandrosta-1,4-diene-17-carboxylic acid

From cis / trans-4- (1-methylethyl) cyclohexanol, (6α, 11β, 16α, 17α) -17-({[(1-ethylpropyl) oxy] carbonyl} oxy) -6,9-difluoro- Prepared using a method similar to that described for 11-hydroxy-16-methyl-3-oxoandrost-1,4-diene-17-carboxylic acid ( Intermediate 3 ). LCMS retention time 3.87 minutes.

Intermediate 12: (6α, 11β, 16α, 17α) -17-({[(1RS, 2RS, 4SR) -bicyclo [2.2.1] hept-2-yloxy] carbonyl} oxy) -6,9-difluoro- 11-Hydroxy-16-methyl-3-oxoandrost-1,4-diene-17-carboxylic acid

From racemic exo-2-norborneol, (6α, 11β, 16α, 17α) -17-({[(1-ethylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16- Prepared using a method similar to that described for methyl-3-oxoandrost-1,4-diene-17-carboxylic acid ( Intermediate 3 ). LCMS retention time 3.54 minutes.

Intermediate 13: (6α, 11β, 16α, 17α) -17-({[(1RS, 2SR, 4SR) -bicyclo [2.2.1] hept-2-yloxy] carbonyl} oxy) -6,9-difluoro- 11-Hydroxy-16-methyl-3-oxoandrost-1,4-diene-17-carboxylic acid

From racemic endo-2-norborneol, (6α, 11β, 16α, 17α) -17-({[(1-ethylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16- Prepared using a method similar to that described for methyl-3-oxoandrost-1,4-diene-17-carboxylic acid ( Intermediate 3 ). LCMS retention time 3.54 minutes.

Intermediate 14: (6α, 11β, 16α, 17α) -6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-[({[(1S, 2R, 4S) -1,7, 7-trimethylbicyclo [2.2.1] hept-2-yl] oxy} carbonyl) oxy] androsta-1,4-diene-17-carboxylic acid

From (-) borneol, (6α, 11β, 16α, 17α) -17-({[(1-ethylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3- Prepared using a method similar to that described for oxoandrosta-1,4-diene-17-carboxylic acid ( Intermediate 3 ). LCMS retention time 3.87 minutes.

Intermediate 15: (6α, 11β, 16α, 17α) -6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-[({[(1R, 2S, 4R) -1,7, 7-trimethylbicyclo [2.2.1] hept-2-yl] oxy} carbonyl) oxy] androsta-1,4-diene-17-carboxylic acid

From (+) borneol, (6α, 11β, 16α, 17α) -17-({[(1-ethylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3- Prepared using a method similar to that described for oxoandrosta-1,4-diene-17-carboxylic acid ( Intermediate 3 ). LCMS retention time 3.81 minutes.

Intermediate 16: (6α, 11β, 16α, 17α) -6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-[({[(1R, 2R, 3R, 5S) -2, 6,6-Trimethylbicyclo [3.1.1] hept-3-yl] oxy} carbonyl) oxy] androsta-1,4-diene-17-carboxylic acid

From (-) isopinocampheol, (6α, 11β, 16α, 17α) -17-({[(1-ethylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16- Prepared using a method similar to that described for methyl-3-oxoandrost-1,4-diene-17-carboxylic acid ( Intermediate 3 ). LCMS retention time 3.87 minutes.

Intermediate 17: (6α, 11β, 16α, 17α) -6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-[({[(1S, 2S, 3S, 5R) -2, 6,6-trimethylbicyclo [3.1.1] hept-3-yl] oxy} carbonyl) oxy] androsta-1,4-diene-17-carboxylic acid;

From (+) isopinocampheol, (6α, 11β, 16α, 17α) -17-({[(1-ethylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16- Prepared using a method similar to that described for methyl-3-oxoandrost-1,4-diene-17-carboxylic acid ( Intermediate 3 ). LCMS retention time 3.86 minutes.

Intermediate 18: (6α, 11β, 16α, 17α) -6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-[({[(1R, 2R, 4S) -1,3, 3-trimethylbicyclo [2.2.1] hept-2-yl] oxy} carbonyl) oxy] androsta-1,4-diene-17-carboxylic acid

From (1R) -endo-(+)-phentyl alcohol, (6α, 11β, 16α, 17α) -17-({[(1-ethylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11 Prepared using a method similar to that described for -hydroxy-16-methyl-3-oxoandrost-1,4-diene-17-carboxylic acid ( Intermediate 3 ). LCMS retention time 3.87 minutes.

Intermediate 19: (6α, 11β, 16α, 17α) -17-({[(trans-4-ethylcyclohexyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3- Oxoandrosta-1,4-diene-17-carboxylic acid

From trans-4-ethylcyclohexanol, (6α, 11β, 16α, 17α) -17-({[(1-ethylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl Prepared using a method similar to that described for -3-oxoandrost-1,4-diene-17-carboxylic acid ( Intermediate 3 ). LCMS retention time 3.78 minutes.

Intermediate 20: (6α, 11β, 16α, 17α) -17-({[(cis-4-ethylcyclohexyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3- Oxoandrosta-1,4-diene-17-carboxylic acid

From cis-4-ethylcyclohexanol, (6α, 11β, 16α, 17α) -17-({[(1-ethylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl Prepared using a method similar to that described for -3-oxoandrost-1,4-diene-17-carboxylic acid ( Intermediate 3 ). LCMS retention time 3.76 minutes.

Intermediate 21: (6α, 11β, 16α, 17α) -6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-({[(1-propylbutyl) oxy] carbonyl} oxy) andro Sta-1,4-diene-17-carboxylic acid

From 4-heptanol, (6α, 11β, 16α, 17α) -17-({[(1-ethylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxo Prepared using a method similar to that described for Androsta-1,4-diene-17-carboxylic acid ( Intermediate 3 ). LCMS retention time 3.65 minutes.

Intermediate 22: (6α, 11β, 16α, 17α) -6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-[({[(1RS, 2RS, 4RS) -1,7, 7-trimethylbicyclo [2.2.1] hept-2-yl] oxy} carbonyl) oxy] androsta-1,4-diene-17-carboxylic acid

A solution of (+/-) isoborneol (154 mg, 1 mmol) and pyridine (81 μl, 1 mmol) in anhydrous dichloromethane (2 ml) was stirred with triphosgene (98 mg, 0.33 mmol) in anhydrous dichloromethane (4 ml) and (ice) To the cooled solution was added in portions over 10 minutes under nitrogen. After 1 hour, about half of the resulting chloroformate solution was dissolved in (6α, 11β, 16α, 17α) -6,9-difluoro-11,17-dihydroxy-16-methyl-3-oxo in pyridine (2 ml). To a solution of androsta-1,4-diene-17-carboxylic acid (200 mg, 0.5 mmol) was added and the mixture was stirred at room temperature overnight. The remainder of the chloroformate solution was then added and after 2 hours the solvent was evaporated in vacuo and the remaining residue was stirred with 2M hydrochloric acid (10 ml). The resulting precipitate was collected by filtration and dried in vacuo to give the title compound as a white solid (341 mg): LCMS retention time 3.85 min.

Intermediate 23: (6α, 11β, 16α, 17α) -6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-({[(1,2,2-trimethylpropyl) oxy] carbonyl } Oxy) androsta-1,4-diene-17-carboxylic acid

From 3,3-dimethyl-2-butanol, (6α, 11β, 16α, 17α) -17-({[(1-ethylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16 Prepared using a method similar to that described for -methyl-3-oxoandrosta-1,4-diene-17-carboxylic acid ( Intermediate 3 ). LCMS retention time 3.54 and 3.54 minutes.

Intermediate 24: (6α, 11β, 16α, 17α) -6,9-difluoro-11-hydroxy-16-methyl-17-[({[1- (1-methylethyl) butyl] oxy} carbonyl) oxy] -3-oxoandrosta-1,4-diene-17-carboxylic acid

From 2-methyl-3-hexanol, (6α, 11β, 16α, 17α) -17-({[(1-ethylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl Prepared using a method similar to that described for -3-oxoandrost-1,4-diene-17-carboxylic acid ( Intermediate 3 ). LCMS retention time 3.66 minutes.

Example
Example 1: (6α, 11β, 16α, 17α) -17-({[(1,1-dimethylethyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3- Oxoandrosta-1,4-diene-17-carboxylic acid cyanomethyl

Sodium carbonate (321 mg, 3 mmol) was added to (6α, 11β, 16α, 17α) -17-({[(1,1-dimethylethyl) oxy] carbonyl} oxy)-in N, N-dimethylformamide (3 ml)- To a solution of 6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost-1,4-diene-17-carboxylic acid ( intermediate 1 ) (150 mg, 0.3 mmol) under nitrogen, The mixture was stirred at room temperature for 15 minutes and then cooled in ice. Bromoacetonitrile (55 μl, 0.815 mmol) was added and the mixture was allowed to warm to room temperature and stirred overnight. Diethylamine (40 μl, 0.51 mmol) was added and the mixture was then added dropwise to 2M hydrochloric acid (20 ml). The product was extracted into ethyl acetate, the extract was dried, evaporated and purified on a Bond Elut cartridge using a 0-100% cyclohexane / ether gradient to give the title compound (123 mg): LCMS Retention time 3.51 min, m / z 536 MH ⁺
Example 2: (6α, 11β, 16α, 17α) -17-({[(1,1-dimethylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3- Oxoandrosta-1,4-diene-17-carboxylic acid cyanomethyl

Example 2 is (6α, 11β, 16α, 17α) -17-({[(1,1-dimethylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3 Prepared from -oxoandrosta-1,4-diene-17-carboxylic acid ( Intermediate 2 ) using a method similar to that described for Example 1 . LCMS retention time 3.59 min, m / z 550 MH ⁺
Example 3: (6α, 11β, 16α, 17α) -17-({[(1-ethylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandro Sta-1,4-diene-17-carboxylate cyanomethyl

Example 3 is (6α, 11β, 16α, 17α) -17-({[(1-ethylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxo Prepared from androsta-1,4-diene-17-carboxylic acid ( Intermediate 3 ) using a method similar to that described for Example 1 . LCMS retention time 3.61 min, m / z 550 MH ⁺

Example 4: (6α, 11β, 16α, 17α) -6,9-difluoro-11-hydroxy-16-methyl-17-[({[2-methyl-1- (1-methylethyl) propyl] oxy} Carbonyl) oxy] -3-oxoandrosta-1,4-diene-17-carboxylate cyanomethyl

Example 4 is (6α, 11β, 16α, 17α) -6,9-difluoro-11-hydroxy-16-methyl-17-[({[2-methyl-1- (1-methylethyl) propyl] oxy } Carbonyl) oxy] -3-oxoandrost-1,4-diene-17-carboxylic acid ( Intermediate 4 ) was prepared using a method similar to that described for Example 1 . LCMS retention time 3.77 min, m / z 578 MH ⁺
Example 5: (6α, 11β, 16α, 17α) -17-({[(2-ethylbutyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrosta Cyanomethyl 1,4-diene-17-carboxylate

Example 5 shows (6α, 11β, 16α, 17α) -17-({[(2-ethylbutyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandro Prepared from sta-1,4-diene-17-carboxylic acid ( Intermediate 5 ) using a method similar to that described for Example 1 . LCMS retention time 3.67 min, m / z 564 MH ⁺
Example 6: (6α, 11β, 16α, 17α) -17-({[(2,2-dimethylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3- Oxoandrosta-1,4-diene-17-carboxylic acid cyanomethyl

Example 6 is (6α, 11β, 16α, 17α) -17-({[(2,2-dimethylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3 Prepared from -oxoandrost-1,4-diene-17-carboxylic acid ( Intermediate 6 ) using a method similar to that described for Example 1 . LCMS retention time 3.56, m / z 550 MH ⁺
Min, m / z 550 MH ⁺
Example 7: (6α, 11β, 16α, 17α) -17-({[(1-ethyl-2-methylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl- Cyanomethyl 3-oxoandrosta-1,4-diene-17-carboxylate

Example 7 shows (6α, 11β, 16α, 17α) -17-({[(1-ethyl-2-methylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl Prepared from -3-oxoandrost-1,4-diene-17-carboxylic acid ( Intermediate 7 ) using a method similar to that described for Example 1 . LCMS retention time 3.69 min, m / z 564 MH ⁺
Example 8: (6α, 11β, 16α, 17α) -17-({[(1,2-dimethylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3- Oxoandrosta-1,4-diene-17-carboxylic acid cyanomethyl

Example 8 is (6α, 11β, 16α, 17α) -17-({[(1,2-dimethylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3 Prepared from -oxoandrosta-1,4-diene-17-carboxylic acid ( Intermediate 8 ) using a method similar to that described for Example 1 . LCMS retention time 3.62 min, m / z 550 MH ⁺
Example 9: (6α, 11β, 16α, 17α) -17-{[(Cyclopentyloxy) carbonyl] oxy} -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost-1,4 Diene-17-carboxylate cyanomethyl

Example 9 includes (6α, 11β, 16α, 17α) -17-{[(cyclopentyloxy) carbonyl] oxy} -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost-1, Prepared from 4-diene-17-carboxylic acid ( Intermediate 9 ) using a method similar to that described for Example 1 . LCMS retention time 3.69 min, m / z 548 MH ⁺
Example 10: (6α, 11β, 16α, 17α) -6,9-difluoro-11-hydroxy-16-methyl-17-[({[(1SR, 2RS) -2-methylcyclohexyl] oxy} carbonyl) oxy ] -3-Oxoandrosta-1,4-diene-17-carboxylic acid cyanomethyl

Example 10 shows (6α, 11β, 16α, 17α) -6,9-difluoro-11-hydroxy-16-methyl-17-[({[(1SR, 2RS) -2-methylcyclohexyl] oxy} carbonyl) Prepared as a mixture of diastereomers from oxy] -3-oxoandrosta-1,4-diene-17-carboxylic acid ( intermediate 10 ) using a method similar to that described for Example 1 did. LCMS retention time 3.67 min, m / z 576 MH ⁺
Example 11: (6α, 11β, 16α, 17α) -6,9-Difluoro-11-hydroxy-16-methyl-17-[({[4- (1-methylethyl) cyclohexyl] oxy} carbonyl) oxy] Cyanomethyl-3-oxoandrosta-1,4-diene-17-carboxylate

Example 11 is (6α, 11β, 16α, 17α) -6,9-difluoro-11-hydroxy-16-methyl-17-[({[4- (1-methylethyl) cyclohexyl] oxy} carbonyl) oxy ] -3-Oxoandrosta-1,4-diene-17-carboxylic acid ( intermediate 11 ) using a method similar to that described for Example 1 using about 3: 1 diastereomers Obtained as a mixture. The diastereomers were then separated by mass directed preparative HPLC to give the following isomers:
Minor isomer Example 11A : LCMS retention time 3.94 min, m / z 604 MH ⁺ . ¹ H-NMR: (DMSO-d ₆ , 400 MHz) 17αcyclohexyl CH proton (adjacent to carbonate) δ 4.67 (m, 1H).

Multimeric isomer Example 11B : LCMS retention time 3.94 min, m / z 604 MH ⁺ . ¹ H-NMR: (DMSO-d ₆ , 400 MHz) 17αcyclohexyl CH proton (adjacent to carbonate) δ 4.33 (m, 1H).

Example 12: (6α, 11β, 16α, 17α) -17-({[(1RS, 2RS, 4SR) -bicyclo [2.2.1] hept-2-yloxy] carbonyl} oxy) -6,9-difluoro- Cyanomethyl 11-hydroxy-16-methyl-3-oxoandrost-1,4-diene-17-carboxylate

Example 12 was prepared from (6α, 11β, 16α, 17α) -17-({[(1RS, 2RS, 4SR) -bicyclo [2.2.1] hept-2-yloxy] carbonyl} oxy) -6,9-difluoro From 11-hydroxy-16-methyl-3-oxoandrost-1,4-diene-17-carboxylic acid ( intermediate 12 ) using a method similar to that described for Example 1 , Produced as a mixture of stereomers. LCMS retention time 3.62 min, m / z 574 MH ⁺
Example 13: (6α, 11β, 16α, 17α) -17-({[(1RS, 2SR, 4SR) -bicyclo [2.2.1] hept-2-yloxy] carbonyl} oxy) -6,9-difluoro- Cyanomethyl 11-hydroxy-16-methyl-3-oxoandrost-1,4-diene-17-carboxylate

Example 13 was prepared from (6α, 11β, 16α, 17α) -17-({[(1RS, 2SR, 4SR) -bicyclo [2.2.1] hept-2-yloxy] carbonyl} oxy) -6,9-difluoro -11-Hydroxy-16-methyl-3-oxoandrost-1,4-diene-17-carboxylic acid ( intermediate 13 ) using a method similar to that described for Example 1 Produced as a mixture of stereomers. LCMS retention time 3.61 min, m / z 574 MH ⁺
Example 14: (6α, 11β, 16α, 17α) -6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-[({[(1S, 2R, 4S) -1,7, 7-trimethylbicyclo [2.2.1] hept-2-yl] oxy} carbonyl) oxy] androsta-1,4-diene-17-carboxylate cyanomethyl

Example 14 was prepared from (6α, 11β, 16α, 17α) -6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-[({[(1S, 2R, 4S) -1,7 , 7-trimethylbicyclo [2.2.1] hept-2-yl] oxy} carbonyl) oxy] androsta-1,4-diene-17-carboxylic acid ( intermediate 14 ) was described for Example 1 . It was manufactured using the same method. The crude product was eluted on a 5 g silica Bond Elute cartridge with a 0-100% ethyl acetate gradient in cyclohexane over 40 min to give the title compound : LCMS retention time 3.92 min, m / z 616 MH ⁺
Example 15: (6α, 11β, 16α, 17α) -6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-[({[(1R, 2S, 4R) -1,7, 7-trimethylbicyclo [2.2.1] hept-2-yl] oxy} carbonyl) oxy] androsta-1,4-diene-17-carboxylate cyanomethyl

Example 15 was prepared from (6α, 11β, 16α, 17α) -6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-[({[(1R, 2S, 4R) -1,7 , 7-trimethylbicyclo [2.2.1] hept-2-yl] oxy} carbonyl) oxy] androsta-1,4-diene-17-carboxylic acid ( intermediate 15 ) was described for Example 1 . It was manufactured using the same method. The crude product was eluted on a 5 g silica Bond Elute cartridge with a 0-100% ethyl acetate gradient in cyclohexane over 40 min to give the title compound : LCMS retention time 3.92 min, m / z 616 MH ⁺
Example 16: (6α, 11β, 16α, 17α) -6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-[({[(1R, 2R, 3R, 5S) -2, 6,6-Trimethylbicyclo [3.1.1] hept-3-yl] oxy} carbonyl) oxy] androsta-1,4-diene-17-carboxylate cyanomethyl

Example 16 was prepared from (6α, 11β, 16α, 17α) -6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-[({[(1R, 2R, 3R, 5S) -1 , 7,7-trimethylbicyclo [2.2.1] hept-2-yl] oxy} carbonyl) oxy] androsta-1,4-diene-17-carboxylic acid ( intermediate 16 ) for Example 1 It was made using the same method as described. The crude product was eluted on a 5 g silica Bond Elute cartridge with a 0-100% ethyl acetate gradient in cyclohexane over 40 min to give the title compound : LCMS retention time 3.97 min, m / z 616 MH ⁺
Example 17: (6α, 11β, 16α, 17α) -6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-[({[(1S, 2S, 3S, 5R) -2, 6,6-Trimethylbicyclo [3.1.1] hept-3-yl] oxy} carbonyl) oxy] androsta-1,4-diene-17-carboxylate cyanomethyl

Example 17 is (6α, 11β, 16α, 17α) -6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-[({[(1S, 2S, 3S, 5R) -1 , 7,7-Trimethylbicyclo [3.1.1] hept-2-yl] oxy} carbonyl) oxy] androsta-1,4-diene-17-carboxylic acid ( intermediate 17 ) for Example 1 Prepared using a similar method as described. The crude product was eluted on a 5 g silica Bond Elute cartridge with a 0-100% ethyl acetate gradient in cyclohexane over 40 min to give the title compound : LCMS retention time 3.97 min, m / z 616 MH ⁺
Example 18: (6α, 11β, 16α, 17α) -6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-[({[(1R, 2R, 4S) -1,3, 3-trimethylbicyclo [2.2.1] hept-2-yl] oxy} carbonyl) oxy] androsta-1,4-diene-17-carboxylate cyanomethyl

Example 18 was prepared from (6α, 11β, 16α, 17α) -6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-[({[(1R, 2R, 4S) -1,7 , 7-trimethylbicyclo [2.2.1] hept-2-yl] oxy} carbonyl) oxy] androsta-1,4-diene-17-carboxylic acid ( intermediate 18 ) was described for Example 1 . It was manufactured using the same method. The crude product was eluted on a 5 g silica Bond Elute cartridge with a 0-100% ethyl acetate gradient in cyclohexane over 40 min to give the title compound : LCMS retention time 3.97 min, m / z 616 MH ⁺
Example 19: (6α, 11β, 16α, 17α) -17-({[(trans-4-ethylcyclohexyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3- Oxoandrosta-1,4-diene-17-carboxylic acid cyanomethyl

Example 19 was prepared from (6α, 11β, 16α, 17α) -17-({[(trans-4-ethylcyclohexyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3 Prepared from -oxoandrost-1,4-diene-17-carboxylic acid ( intermediate 19 ) using a method similar to that described for Example 1 . The crude product was eluted on a 5 g silica Bond Elute cartridge with a 0-100% diethyl ether gradient in cyclohexane over 40 min to give the title compound : LCMS retention time 3.90 min, m / z 590 MH ⁺
Example 20: (6α, 11β, 16α, 17α) -17-({[(cis-4-ethylcyclohexyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3- Oxoandrosta-1,4-diene-17-carboxylic acid cyanomethyl

Example 20 is directed to (6α, 11β, 16α, 17α) -17-({[(cis-4-ethylcyclohexyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3 Prepared from -oxoandrosta-1,4-diene-17-carboxylic acid ( Intermediate 20 ) using a method similar to that described for Example 1 . The crude product was eluted on a 5 g silica Bond Elute cartridge with a 0-100% diethyl ether gradient in cyclohexane over 40 min to give the title compound : LCMS retention time 3.86 min, m / z 590 MH ⁺
Example 21: (6α, 11β, 16α, 17α) -6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-({[(1-propylbutyl) oxy] carbonyl} oxy) andro Sta-1,4-diene-17-carboxylate cyanomethyl

Example 21 is (6α, 11β, 16α, 17α) -6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-({[(1-propylbutyl) oxy] carbonyl} oxy) Prepared from androsta-1,4-diene-17-carboxylic acid ( intermediate 21 ) using a method similar to that described for Example 1 . The crude product was eluted on a 5 g silica Bond Elute cartridge with a 0-100% diethyl ether gradient in cyclohexane over 40 min to give the title compound : LCMS retention time 3.82 min, m / z 578 MH ⁺
Example 22: (6α, 11β, 16α, 17α) -6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-[({[(1R, 2R, 4R) -1,7, 7-trimethylbicyclo [2.2.1] hept-2-yl] oxy} carbonyl) oxy] androsta-1,4-diene-17-carboxylate cyanomethyl

Example 22 was prepared from (6α, 11β, 16α, 17α) -6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-[({[(1R, 2R, 4R) -1,7 , 7-trimethylbicyclo [2.2.1] hept-2-yl] oxy} carbonyl) oxy] androsta-1,4-diene-17-carboxylic acid ( intermediate 22 ) was described for Example 1 . Prepared as a mixture of diastereomers using the same method as above. The crude product was eluted on a 5 g silica Bond Elute cartridge with a 0-100% ethyl acetate gradient in cyclohexane over 40 minutes to give the title compound :
The diastereomers were then separated using normal phase HPLC to give:
Example 22A : LCMS retention time 3.93 minutes, m / z 616 MH ⁺ . ¹ H-NMR: (DMSO-d ₆ , 400 MHz) 17β cyanomethylene protons δ 5.03 (d, 16 Hz) and δ 5.00 (d, 16 Hz)
Example 22B : LCMS retention time 3.93 minutes, m / z 616 MH ⁺ . ¹ H-NMR: (DMSO-d ₆ , 400 MHz) 17β cyanomethylene protons δ 5.07 (d, 16 Hz) and δ 5.01 (d, 16 Hz)
Example 23: (6α, 11β, 16α, 17α) -6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-({[(1,2,2-trimethylpropyl) oxy] carbonyl } Oxy) androsta-1,4-diene-17-carboxylate cyanomethyl

Example 23 was prepared from (6α, 11β, 16α, 17α) -6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-({[(1,2,2-trimethylpropyl) oxy] Prepared as a crude mixture of diastereomers from carbonyl} oxy) androsta-1,4-diene-17-carboxylic acid ( intermediate 23 ) using methods similar to those described for Example 1 . .

The crude diastereomers were then separated using normal phase HPLC to give:
Example 23A : LCMS retention time 3.88 minutes, m / z 564 MH ⁺ . ¹ H-NMR: (DMSO-d ₆ , 400 MHz) 17 β cyanomethylene proton δ 5.01 (s, 2H)
Example 23B : LCMS retention time 3.85 minutes, m / z 564 MH ^<+> . ¹ H-NMR: (DMSO-d ₆ , 400 MHz) 17 β cyanomethylene protons δ 5.10 (d, 16 Hz, 1H) and δ 5.01 (d, 16 Hz, 1H).

Example 24: (6α, 11β, 16α, 17α) -6,9-difluoro-11-hydroxy-16-methyl-17-[({[1- (1-methylethyl) butyl] oxy} carbonyl) oxy] Cyanomethyl-3-oxoandrosta-1,4-diene-17-carboxylate

Example 24 is (6α, 11β, 16α, 17α) -6,9-difluoro-11-hydroxy-16-methyl-17-[({[1- (1-methylethyl) butyl] oxy} carbonyl) oxy Prepared as a mixture of diastereomers from a similar method as described for Example 1 from -3-oxoandrost-1,4-diene-17-carboxylic acid ( Intermediate 24 ) . The crude product was eluted on a 10 g silica Bond Elute cartridge with a 0-100% ethyl acetate gradient in cyclohexane over 40 min to give the title compound : LCMS retention time 3.79 min, m / z 578 MH ⁺
Pharmacological activity Pharmacological activity can be assessed in a functional in vitro assay of glucocorticoid agonist activity.

Assay of transcriptional repression activity of glucocorticoid agonists
A functional assay based on the assay described by KPRay et al. In Biochem J. (1997), 328, 707-715 provides a measure of the transcriptional repressive activity of glucocorticoid agonists. A549 cells stably transfected with a reporter gene containing an NF-κB responsive element derived from the ELAM gene promoter bound to sPAP (secreted alkaline phosphatase) were treated with an appropriate dose of test compound for 1 hour at 37 ° C. To do. Cells are then stimulated with tumor necrosis factor (TNF, 10 ng / ml) for 16 hours, and the alkaline phosphatase produced at that time is measured by a standard colorimetric assay. Dose response curves were generated from which EC ₅₀ values were estimated.

The pEC ₅₀ values for the compounds of Examples 1-24 were> 7.5 in this assay.

The pEC ₅₀ values for the compounds of Examples 1-10, 11B, 12 and 13 were> 9.5 in this assay.

The pEC ₅₀ value of the combination of Examples 1, 2 and 13 was> 10 in this assay.

Assay of transcriptional activation activity of glucocorticoid agonists
A functional assay based on the assay described by RJH Austin et al. In Eur Resp J. (2002), 20, 1386-1392 measures the ability of a compound to directly transcriptionally activate gene expression. A549 cells stably transfected with a reporter gene containing a mouse mammary tumor virus long terminal repeat (MMTV-LTR) conjugated to Renilla luciferase were treated with an appropriate dose of test compound for 6 hours at 37 ° C. The amount of luciferase activity present in the cells is then determined by measuring the light emitted after incubation with a suitable substrate. Dose response curves were generated from which EC ₅₀ values were estimated. And then the maximum response to dexamethasone (100%) is calculated.

The compounds of Examples 1-24 showed <40% maximal response in this assay.

The compounds of Examples 1-4, 6, 10-18, and 20-23B showed <10% maximal response in this assay.

A T225 flask of CV-1 cells with an assay density of 80% progesterone receptor activity was washed with PBS, separated from the flask with 0.25% trypsin, and counted with Sysmex KX-21N. Cells were diluted at 140 cells / μl in DMEM containing 10% high clone, 2 mM L-glutamate and 1% Pen / Strep and transduced with 10% PRb-BacMam and 10% MMTV-BacMam. 70 ml of suspended cells were dispensed into each well of a white Nunc 384 well plate containing the required concentration of compound. After 24 hours, 10 μl of Steady Glo was added to each well of the plate. Plates were incubated for 10 minutes in the dark before reading on a Viewlux reader. Dose response curves were generated from which pEC ₅₀ values were estimated.

The pEC ₅₀ values of the compounds of Examples 1, 2, 5-13, 15-18 and 22A-24 were <7 in this assay.

  Throughout the specification and claims, unless the context requires otherwise, variations such as “comprise” and “comprises” and “comprising” are not intended to imply any stated integer or means or group of integers. It will be understood that it is meant to include, but is not meant to exclude any other integer or means or group of integers or means.

  The application of which this description and claims form part may be used as a basis for priority in respect of any subsequent application. Such subsequent applications may be directed to any spot color or combination of spot colors described herein. They may take the form of product, composition or use claims and may, by way of example and without exception, include the claims.

  The patents and patent applications described in this application are hereby incorporated by reference.

Claims (24)

Compounds of formula (I):

(Where
R ₁ represents a C ₄ -C ₇ branched alkyl group, a bicycloalkyl group, or a C ₅ -C ₆ cycloalkyl group optionally substituted with a C ₁ -C ₄ alkyl group;
R ₂ represents hydrogen or a methyl group that may be either α or β configuration;
R ₃ and R ₄ are the same or different groups and each independently represents a hydrogen, halogen or methyl group;
And

Represents a single bond or a double bond);
Or a physiologically acceptable solvate thereof. R ₁ is 1,1-dimethylethyl, 1-ethylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 1,2-dimethylpropyl, 1-ethyl-2-methylpropyl, 2-methyl-1 The compound according to claim 1, which represents a C ₄ -C ₇ branched alkyl group which is a-(1-methylethyl) propyl, 2-ethylbutyl, 1-propylbutyl or 1- (1-methylethyl) butyl group. . The compound of claim 1, wherein R ₁ represents a C ₅ -C ₆ cycloalkyl group optionally substituted with a C ₁ -C ₃ alkyl group. The compound according to claim 3, wherein R ₁ represents cyclopentyl, (1SR, 2RS) -2-methylcyclohexyl, 4- (1-methylethyl) cyclohexyl, trans-4-ethylcyclohexyl or cis-4-ethylcyclohexyl. . R ₁ is (1RS, 2RS, 4SR) -bicyclo [2.2.1] hept-2-yl, (1RS, 2SR, 4SR) -bicyclo [2.2.1] hept-2-yl, (1S, 2R, 4S) Bicyclo, which is a -1,7,7-trimethylbicyclo [2.2.1] hept-2-yl or (1R, 2S, 4R) -1,7,7-trimethylbicyclo [2.2.1] hept-2-yl group 2. A compound according to claim 1 which represents an alkyl group. R ₁ is 1,1-dimethylethyl, 1,1-dimethylpropyl, 1-ethylpropyl, 2-methyl-1- (1-methylethyl) propyl, 2,2-dimethylpropyl, (1SR, 2RS) -2 -Methylcyclohexyl, 4- (1-methylethyl) cyclohexyl isomer B or (1RS, 2RS, 4SR) -bicyclo [2.2.1] hept-2-yl or (1RS, 2SR, 4SR) -bicyclo [2.2.1 The compound according to any one of claims 1 to 5, which represents a hept-2-yl group. The compound according to claim 1, wherein R ₁ is a 1,1-dimethylpropyl group. The compound according to claim 1, wherein R ₁ is a 1,1-dimethylethyl group. The compound according to any one of claims 1 to 8, wherein R ₂ represents a methyl group in an α-configuration. R ₃ and R ₄ are fluorine both A compound according to any one of claims 1 to 9.

10. The compound according to any one of claims 1 to 9, wherein represents a double bond. (6α, 11β, 16α, 17α) -17-({[(1,1-dimethylethyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost- Cyanomethyl 1,4-diene-17-carboxylate;
(6α, 11β, 16α, 17α) -17-({[(1,1-dimethylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost- Cyanomethyl 1,4-diene-17-carboxylate;
(6α, 11β, 16α, 17α) -17-({[(1-Ethylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost-1, Cyanomethyl 4-diene-17-carboxylate;
(6α, 11β, 16α, 17α) -6,9-Difluoro-11-hydroxy-16-methyl-17-[({[2-methyl-1- (1-methylethyl) propyl] oxy} carbonyl) oxy] Cyanomethyl-3-oxoandrost-1,4-diene-17-carboxylate;
(6α, 11β, 16α, 17α) -17-({[(2-Ethylbutyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost-1,4 -Cyanomethyl diene-17-carboxylate;
(6α, 11β, 16α, 17α) -17-({[(2,2-dimethylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost- Cyanomethyl 1,4-diene-17-carboxylate;
(6α, 11β, 16α, 17α) -17-({[(1-Ethyl-2-methylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandro Sta-1,4-diene-17-carboxylate cyanomethyl;
(6α, 11β, 16α, 17α) -17-({[(1,2-dimethylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost- Cyanomethyl 1,4-diene-17-carboxylate; and
(6α, 11β, 16α, 17α) -17-{[(Cyclopentyloxy) carbonyl] oxy} -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost-1,4-diene-17 -Cyanomethyl carboxylate;
(6α, 11β, 16α, 17α) -6,9-Difluoro-11-hydroxy-16-methyl-17-[({[(1SR, 2RS) -2-methylcyclohexyl] oxy} carbonyl) oxy] -3- Oxoandrosta-1,4-diene-17-carboxylate cyanomethyl;
(6α, 11β, 16α, 17α) -6,9-Difluoro-11-hydroxy-16-methyl-17-[({[4- (1-methylethyl) cyclohexyl] oxy} carbonyl) oxy] -3-oxo Androsta-1,4-diene-17-carboxylate cyanomethyl;
(6α, 11β, 16α, 17α) -17-({[(1RS, 2RS, 4SR) -bicyclo [2.2.1] hept-2-yloxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy- Cyanomethyl 16-methyl-3-oxoandrosta-1,4-diene-17-carboxylate;
(6α, 11β, 16α, 17α) -17-({[(1RS, 2SR, 4SR) -bicyclo [2.2.1] hept-2-yloxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy- Cyanomethyl 16-methyl-3-oxoandrosta-1,4-diene-17-carboxylate;
(6α, 11β, 16α, 17α) -6,9-Difluoro-11-hydroxy-16-methyl-3-oxo-17-[({[(1S, 2R, 4S) -1,7,7-trimethylbicyclo [2.2.1] hept-2-yl] oxy} carbonyl) oxy] androsta-1,4-diene-17-carboxylate cyanomethyl;
(6α, 11β, 16α, 17α) -6,9-Difluoro-11-hydroxy-16-methyl-3-oxo-17-[({[(1R, 2S, 4R) -1,7,7-trimethylbicyclo [2.2.1] hept-2-yl] oxy} carbonyl) oxy] androsta-1,4-diene-17-carboxylate cyanomethyl;
(6α, 11β, 16α, 17α) -6,9-Difluoro-11-hydroxy-16-methyl-3-oxo-17-[({[(1R, 2R, 3R, 5S) -2,6,6- Trimethylbicyclo [3.1.1] hept-3-yl] oxy} carbonyl) oxy] androsta-1,4-diene-17-carboxylate cyanomethyl;
(6α, 11β, 16α, 17α) -6,9-Difluoro-11-hydroxy-16-methyl-3-oxo-17-[({[(1S, 2S, 3S, 5R) -2,6,6- Trimethylbicyclo [3.1.1] hept-3-yl] oxy} carbonyl) oxy] androsta-1,4-diene-17-carboxylate cyanomethyl;
(6α, 11β, 16α, 17α) -6,9-Difluoro-11-hydroxy-16-methyl-3-oxo-17-[({[(1R, 2R, 4S) -1,3,3-trimethylbicyclo [2.2.1] hept-2-yl] oxy} carbonyl) oxy] androsta-1,4-diene-17-carboxylate cyanomethyl;
(6α, 11β, 16α, 17α) -17-({[(trans-4-ethylcyclohexyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost- Cyanomethyl 1,4-diene-17-carboxylate;
(6α, 11β, 16α, 17α) -17-({[(cis-4-ethylcyclohexyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost- Cyanomethyl 1,4-diene-17-carboxylate;
(6α, 11β, 16α, 17α) -6,9-Difluoro-11-hydroxy-16-methyl-3-oxo-17-({[(1-propylbutyl) oxy] carbonyl} oxy) androsta-1, Cyanomethyl 4-diene-17-carboxylate;
(6α, 11β, 16α, 17α) -6,9-Difluoro-11-hydroxy-16-methyl-3-oxo-17-[({[(1R, 2R, 4R) -1,7,7-trimethylbicyclo [2.2.1] hept-2-yl] oxy} carbonyl) oxy] androsta-1,4-diene-17-carboxylate cyanomethyl;
(6α, 11β, 16α, 17α) -6,9-Difluoro-11-hydroxy-16-methyl-3-oxo-17-[({[(1S, 2S, 4S) -1,7,7-trimethylbicyclo [2.2.1] hept-2-yl] oxy} carbonyl) oxy] androsta-1,4-diene-17-carboxylate cyanomethyl;
(6α, 11β, 16α, 17α) -6,9-Difluoro-11-hydroxy-16-methyl-3-oxo-17-({[(1,2,2-trimethylpropyl) oxy] carbonyl} oxy) andro Sta-1,4-diene-17-carboxylate cyanomethyl; or
(6α, 11β, 16α, 17α) -6,9-Difluoro-11-hydroxy-16-methyl-17-[({[1- (1-methylethyl) butyl] oxy} carbonyl) oxy] -3-oxo A compound which is androsta-1,4-diene-17-carboxylate cyanomethyl. (6α, 11β, 16α, 17α) -17-({[(1-Ethylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost-1, Cyanomethyl 4-diene-17-carboxylate;
(6α, 11β, 16α, 17α) -6,9-Difluoro-11-hydroxy-16-methyl-17-[({[2-methyl-1- (1-methylethyl) propyl] oxy} carbonyl) oxy] Cyanomethyl-3-oxoandrost-1,4-diene-17-carboxylate;
(6α, 11β, 16α, 17α) -6,9-Difluoro-11-hydroxy-16-methyl-17-[({[4- (1-methylethyl) cyclohexyl] oxy} carbonyl) oxy] -3-oxo Androsta-1,4-diene-17-carboxylate cyanomethyl isomer A;
(6α, 11β, 16α, 17α) -6,9-Difluoro-11-hydroxy-16-methyl-17-[({[4- (1-methylethyl) cyclohexyl] oxy} carbonyl) oxy] -3-oxo Androsta-1,4-diene-17-carboxylate cyanomethyl isomer B;
(6α, 11β, 16α, 17α) -17-({[(2-Ethylbutyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost-1,4 -Cyanomethyl diene-17-carboxylate;
(6α, 11β, 16α, 17α) -6,9-Difluoro-11-hydroxy-16-methyl-17-[({[(1SR, 2RS) -2-methylcyclohexyl] oxy} carbonyl) oxy] -3- Oxoandrosta-1,4-diene-17-carboxylate cyanomethyl;
(6α, 11β, 16α, 17α) -17-({[(2,2-dimethylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost- Cyanomethyl 1,4-diene-17-carboxylate;
(6α, 11β, 16α, 17α) -17-({[(1RS, 2RS, 4SR) -bicyclo [2.2.1] hept-1-yloxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy- Cyanomethyl 16-methyl-3-oxoandrosta-1,4-diene-17-carboxylate;
(6α, 11β, 16α, 17α) -17-({[(1RS, 2SR, 4SR) -bicyclo [2.2.1] hept-1-yloxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy- Cyanomethyl 16-methyl-3-oxoandrosta-1,4-diene-17-carboxylate;
(6α, 11β, 16α, 17α) -17-({[(1,1-dimethylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost- Cyanomethyl 1,4-diene-17-carboxylate;
(6α, 11β, 16α, 17α) -17-({[(1,1-dimethylethyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost- Cyanomethyl 1,4-diene-17-carboxylate;
(6α, 11β, 16α, 17α) -17-({[(1-Ethyl-2-methylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandro Sta-1,4-diene-17-carboxylate cyanomethyl;
(6α, 11β, 16α, 17α) -17-({[(1,2-dimethylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost- Cyanomethyl 1,4-diene-17-carboxylate;
(6α, 11β, 16α, 17α) -17-{[(Cyclopentyloxy) carbonyl] oxy} -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost-1,4-diene-17 -Cyanomethyl carboxylate;
(6α, 11β, 16α, 17α) -6,9-Difluoro-11-hydroxy-16-methyl-3-oxo-17-[({[(1S, 2R, 4S) -1,7,7-trimethylbicyclo [2.2.1] hept-2-yl] oxy} carbonyl) oxy] androsta-1,4-diene-17-carboxylate cyanomethyl;
(6α, 11β, 16α, 17α) -6,9-Difluoro-11-hydroxy-16-methyl-3-oxo-17-[({[(1R, 2S, 4R) -1,7,7-trimethylbicyclo [2.2.1] hept-2-yl] oxy} carbonyl) oxy] androsta-1,4-diene-17-carboxylate cyanomethyl;
(6α, 11β, 16α, 17α) -17-({[(trans-4-ethylcyclohexyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost- Cyanomethyl 1,4-diene-17-carboxylate;
(6α, 11β, 16α, 17α) -17-({[(cis-4-ethylcyclohexyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost- Cyanomethyl 1,4-diene-17-carboxylate;
(6α, 11β, 16α, 17α) -6,9-Difluoro-11-hydroxy-16-methyl-3-oxo-17-({[(1-propylbutyl) oxy] carbonyl} oxy) androsta-1, Cyanomethyl 4-diene-17-carboxylate; or
(6α, 11β, 16α, 17α) -6,9-Difluoro-11-hydroxy-16-methyl-17-[({[1- (1-methylethyl) butyl] oxy} carbonyl) oxy] -3-oxo 13. A compound according to claim 12, which is cyanomethyl androsta-1,4-diene-17-carboxylate. (6α, 11β, 16α, 17α) -17-({[(1,1-dimethylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost- Cyanomethyl 1,4-diene-17-carboxylate;
(6α, 11β, 16α, 17α) -17-({[(1,1-dimethylethyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost- Cyanomethyl 1,4-diene-17-carboxylate;
(6α, 11β, 16α, 17α) -17-({[(1-Ethylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost-1, Cyanomethyl 4-diene-17-carboxylate;
(6α, 11β, 16α, 17α) -6,9-Difluoro-11-hydroxy-16-methyl-17-[({[2-methyl-1- (1-methylethyl) propyl] oxy} carbonyl) oxy] Cyanomethyl-3-oxoandrost-1,4-diene-17-carboxylate;
(6α, 11β, 16α, 17α) -17-({[(2,2-dimethylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost- Cyanomethyl 1,4-diene-17-carboxylate;
(6α, 11β, 16α, 17α) -6,9-Difluoro-11-hydroxy-16-methyl-17-[({[(1SR, 2RS) -2-methylcyclohexyl] oxy} carbonyl) oxy] -3- Oxoandrosta-1,4-diene-17-carboxylate cyanomethyl;
(6α, 11β, 16α, 17α) -6,9-Difluoro-11-hydroxy-16-methyl-17-[({[4- (1-methylethyl) cyclohexyl] oxy} carbonyl) oxy] -3-oxo Androsta-1,4-diene-17-carboxylate cyanomethyl isomer B;
(6α, 11β, 16α, 17α) -17-({[(1RS, 2RS, 4SR) -bicyclo [2.2.1] hept-2-yloxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy- Cyanomethyl 16-methyl-3-oxoandrosta-1,4-diene-17-carboxylate; or
(6α, 11β, 16α, 17α) -17-({[(1RS, 2SR, 4SR) -bicyclo [2.2.1] hept-2-yloxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy- 14. The compound according to claim 13, which is cyanomethyl 16-methyl-3-oxoandrost-1,4-diene-17-carboxylate. (6α, 11β, 16α, 17α) -17-({[(1,1-dimethylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost- Cyanomethyl 1,4-diene-17-carboxylate;
(6α, 11β, 16α, 17α) -17-({[(1,1-dimethylethyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost- Cyanomethyl 1,4-diene-17-carboxylate; or
(6α, 11β, 16α, 17α) -17-({[(1RS, 2SR, 4SR) -bicyclo [2.2.1] hept-2-yloxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy- 15. A compound according to any one of claims 12 to 14 which is cyanomethyl 16-methyl-3-oxoandrost-1,4-diene-17-carboxylate.   (6α, 11β, 16α, 17α) -17-({[(1,1-dimethylpropyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost- The compound according to any one of claims 12 to 14, which is cyanomethyl 1,4-diene-17-carboxylate.   (6α, 11β, 16α, 17α) -17-({[(1,1-dimethylethyl) oxy] carbonyl} oxy) -6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrost- The compound according to any one of claims 12 to 14, which is cyanomethyl 1,4-diene-17-carboxylate.   18. A compound of formula (I) or a physiologically acceptable solvate thereof according to any one of claims 1 to 17 for use in animal or human medicine.   Use of a compound of formula (I) or a physiologically acceptable solvate thereof according to any one of claims 1 to 17 for the manufacture of a medicament for the treatment of inflammatory and / or allergic conditions.   18. A compound of formula (I) or a physiologically acceptable solvate thereof according to any one of claims 1 to 17, optionally with one or more physiologically acceptable diluents or carriers. A pharmaceutical composition comprising a mixture.   A compound of formula (I) according to any one of claims 1 to 17, or a physiologically acceptable solvate thereof, and optionally a fluorocarbon or hydrogen-containing chlorofluorocarbon as a propellant, optionally at the interface A pharmaceutical aerosol formulation comprising in combination with an active agent and / or a co-solvent.   The pharmaceutical composition according to claim 21, further comprising another therapeutically active agent. The pharmaceutical composition according to claim 22, wherein said another therapeutically active agent is a β ₂ -adrenergic receptor agonist. Carboxylic acid of formula (II)

(Wherein R ₁ , R ₂ , R ₃ , R ₄ and

Comprises reacting either is as defined in item 1) of formula L-CH ₂ -CN in a compound of claims 1 to 10 (wherein, L is a leaving group), the formula (I ).